Medicinal (Radio) Chemistry: Building Radiopharmaceuticals for the
Future

Martha   Sahylí Ortega   Pijeira; Paulo   Sérgio Gonçalves   Nunes; Samila   Leon   Chaviano; Aida   M. Abreu   Diaz; Jean   N.   DaSilva; Eduardo      Ricci-Junior; Luciana   Magalhães Rebelo   Alencar; Xiaoyuan      Chen; Ralph      Santos-Oliveira
Abstract

Radiopharmaceuticals are increasingly playing a leading role in diagnosing, monitoring, and treating disease. In comparison with conventional pharmaceuticals, the development of radiopharmaceuticals does follow the principles of medicinal chemistry in the context of imaging-altered physiological processes. The design of a novel radiopharmaceutical has several steps similar to conventional drug discovery and some particularity. In the present work, we revisited the insights of medicinal chemistry in the current radiopharmaceutical development giving examples in oncology, neurology, and cardiology. In this regard, we overviewed the literature on radiopharmaceutical development to study overexpressed targets such as prostate-specific membrane antigen and fibroblast activation protein in cancer; β-amyloid plaques and tau protein in brain disorders; and angiotensin II type 1 receptor in cardiac disease. The work addresses concepts in the field of radiopharmacy with a special focus on the potential use of radiopharmaceuticals for nuclear imaging and theranostics.
Keywords: Medicinal chemistry of radiopharmaceuticals, radiopharmaceutical development, SPECT, PET, theranostics, radio chemistry.
[1]
WHO. Monogragraps: Radiopharmaceuticals. ,  Available from: https://digicollections.net/phint/2020/index.html#d/b.6.3.1.1.1 (Accessed on: Feb 7, 2022).

[2]
Qin, X.; Han, D.; Wu, J.C. Molecular imaging of cardiac regenerative medicine. Curr. Opin. Biomed. Eng.,  2019, 9, 66-73.
 [http://dx.doi.org/10.1016/j.cobme.2019.04.006]

[3]
Danad, I.; Raijmakers, P.G.; Driessen, R.S.; Leipsic, J.; Raju, R.; Naoum, C.; Knuuti, J.; Mäki, M.; Underwood, R.S.; Min, J.K.; Elmore, K.; Stuijfzand, W.J.; van Royen, N.; Tulevski, I.I.; Somsen, A.G.; Huisman, M.C.; van Lingen, A.A.; Heymans, M.W.; van de Ven, P.M.; van Kuijk, C.; Lammertsma, A.A.; van Rossum, A.C.; Knaapen, P. Comparison of coronary CT angiography, SPECT, PET, and hybrid imaging for diagnosis of ischemic heart disease determined by fractional flow reserve. JAMA Cardiol.,  2017, 2(10), 1100-1107.
 [http://dx.doi.org/10.1001/jamacardio.2017.2471] [PMID: 28813561]

[4]
Al Badarin, F.J.; Malhotra, S. Diagnosis and prognosis of coronary artery disease with SPECT and PET. Curr. Cardiol. Rep.,  2019, 21(7), 57.
 [http://dx.doi.org/10.1007/s11886-019-1146-4] [PMID: 31104158]

[5]
Sheikhbahaei, S.; Taghipour, M.; Ahmad, R.; Fakhry, C.; Kiess, A.P.; Chung, C.H.; Subramaniam, R.M. Diagnostic accuracy of follow-up FDG PET or PET/CT in patients with head and neck cancer after definitive treatment: A systematic review and meta-analysis. AJR Am. J. Roentgenol.,  2015, 205(3), 629-639.
 [http://dx.doi.org/10.2214/AJR.14.14166] [PMID: 26295652]

[6]
Hope, T.A.; Goodman, J.Z.; Allen, I.E.; Calais, J.; Fendler, W.P.; Carroll, P.R. Meta-analysis of 68 Ga-PSMA-11 PET accuracy for the detection of prostate cancer validated by histopathology. J. Nucl. Med.,  2019, 60(6), 786-793.
 [http://dx.doi.org/10.2967/jnumed.118.219501] [PMID: 30530831]

[7]
Rager, O.; Lee-Felker, S.A.; Tabouret-Viaud, C.; Felker, E.R.; Poncet, A.; Amzalag, G.; Garibotto, V.; Zaidi, H.; Walter, M.A. Accuracy of whole-body HDP SPECT/CT, FDG PET/CT, and their combination for detecting bone metastases in breast cancer: An intra-personal comparison. Am. J. Nucl. Med. Mol. Imaging,  2018, 8(3), 159-168.
 [PMID: 30042868]

[8]
Gherghe, M.; Mutuleanu, M.D.; Stanciu, A.E.; Irimescu, I.; Lazar, A.; Bacinschi, X.; Anghel, R.M. Quantitative analysis of SPECT-CT data in metastatic breast cancer patients—the clinical significance. Cancers.,  2022, 14(2), 273.
 [http://dx.doi.org/10.3390/cancers14020273] [PMID: 35053436]

[9]
Zhang-Yin, J.T.; Girard, A.; Bertaux, M. What does PET imaging bring to neuro-oncology in 2022? a review. Cancers.,  2022, 14(4), 879.
 [http://dx.doi.org/10.3390/cancers14040879] [PMID: 35205625]

[10]
Kerstens, V.S.; Varrone, A. Dopamine transporter imaging in neurodegenerative movement disorders: PET vs. SPECT. Clin. Transl. Imaging,  2020, 8(5), 349-356.
 [http://dx.doi.org/10.1007/s40336-020-00386-w]

[11]
Minoshima, S.; Mosci, K.; Cross, D.; Thientunyakit, T. Brain [F-18]FDG PET for clinical dementia workup: Differential diagnosis of Alzheimer’s disease and other types of dementing disorders. Semin. Nucl. Med.,  2021, 51(3), 230-240.
 [http://dx.doi.org/10.1053/j.semnuclmed.2021.01.002] [PMID: 33546814]

[12]
Ferrando, R.; Damian, A. Brain SPECT as a biomarker of neurodegeneration in dementia in the era of molecular imaging: Still a valid option? Front. Neurol.,  2021, 12, 629442.
 [http://dx.doi.org/10.3389/fneur.2021.629442] [PMID: 34040574]

[13]
Willmann, J.K.; van Bruggen, N.; Dinkelborg, L.M.; Gambhir, S.S. Molecular imaging in drug development. Nat. Rev. Drug Discov.,  2008, 7(7), 591-607.
 [http://dx.doi.org/10.1038/nrd2290] [PMID: 18591980]

[14]
Waaijer, S.J.H.; Kok, I.C.; Eisses, B.; Schröder, C.P.; Jalving, M.; Brouwers, A.H.; Lub-de Hooge, M.N.; de Vries, E.G.E. Molecular imaging in cancer drug development. J. Nucl. Med.,  2018, 59(5), 726-732.
 [http://dx.doi.org/10.2967/jnumed.116.188045] [PMID: 29371402]

[15]
Son, H.; Jang, K.; Lee, H.; Kim, S.E.; Kang, K.W.; Lee, H. Use of molecular imaging in clinical drug development: A systematic review. Nucl. Med. Mol. Imaging,  2019, 53(3), 208-215.
 [http://dx.doi.org/10.1007/s13139-019-00593-y] [PMID: 31231441]

[16]
Saw, M.M. Medicinal radiopharmaceutical chemistry of metal radiopharmaceuticals. Cosmos.,  2012, 8(1), 11-81.
 [http://dx.doi.org/10.1142/S0219607712300044]

[17]
Imming, P. Medicinal chemistry: Definitions and objectives, drug activity phases, drug classification systems. In: The Practice of Medicinal Chemistry; Wermut, C.G., Ed.; Academic Press, 2008; pp. 63-72.
 [http://dx.doi.org/10.1016/B978-0-12-374194-3.00002-0]

[18]
Farahani, A.M.; Maleki, F.; Sadeghzadeh, N. The influence of different spacers on biological profile of peptide radiopharmaceuticals for diagnosis and therapy of human cancers. Anti-Cancer Agents Med. Chem.,  2020, 20, 402-416.

[19]
Evans, B.J.; King, A.T.; Katsifis, A.; Matesic, L.; Jamie, J.F. Methods to enhance the metabolic stability of peptide-based PET radiopharmaceuticals. Molecules.,  2020, 25(10), 2314.
 [http://dx.doi.org/10.3390/molecules25102314] [PMID: 32423178]

[20]
Valenta, I.; Pacher, P.; Dilsizian, V.; Schindler, T.H. Novel myocardial PET/CT receptor imaging and potential therapeutic targets. Curr. Cardiol. Rep.,  2019, 21(7), 55.
 [http://dx.doi.org/10.1007/s11886-019-1148-2] [PMID: 31104205]

[21]
Coenen, H.H.; Gee, A.D.; Adam, M.; Antoni, G.; Cutler, C.S.; Fujibayashi, Y.; Jeong, J.M.; Mach, R.H.; Mindt, T.L.; Pike, V.W.; Windhorst, A.D. Consensus nomenclature rules for radiopharmaceutical chemistry — Setting the record straight. Nucl. Med. Biol.,  2017, 55, v-xi.
 [http://dx.doi.org/10.1016/j.nucmedbio.2017.09.004] [PMID: 29074076]

[22]
Willowson, K.P. Production of radionuclides for clinical nuclear medicine. Eur. J. Phys.,  2019, 40(4), 043001.
 [http://dx.doi.org/10.1088/1361-6404/ab169b]

[23]
Talip, Z.; Favaretto, C.; Geistlich, S.; Meulen, N.P. A step-by-step guide for the novel radiometal production for medical applications: Case studies with 68Ga, 44Sc, 177Lu and 161Tb. Molecules.,  2020, 25(4), 966.
 [http://dx.doi.org/10.3390/molecules25040966] [PMID: 32093425]

[24]
Dash, A.; Chakravarty, R. Radionuclide generators: The prospect of availing PET radiotracers to meet current clinical needs and future research demands. Am. J. Nucl. Med. Mol. Imaging,  2019, 9(1), 30-66.
 [PMID: 30911436]

[25]
Conti, M.; Eriksson, L. Physics of pure and non-pure positron emitters for PET: A review and a discussion. EJNMMI Phys.,  2016, 3(1), 8.
 [http://dx.doi.org/10.1186/s40658-016-0144-5] [PMID: 27271304]

[26]
Dubost, E.; McErlain, H.; Babin, V.; Sutherland, A.; Cailly, T. Recent advances in synthetic methods for radioiodination. J. Org. Chem.,  2020, 85(13), 8300-8310.
 [http://dx.doi.org/10.1021/acs.joc.0c00644] [PMID: 32369696]

[27]
Al-Alawy, I.T.; Mohammed, R.S. Nuclear data relevant to the production of radioiodine I-123, I-125 by indirect route and medical applications. Int. Lett. Chem. Phys.,  2016, 63, 90-97.
 [http://dx.doi.org/10.56431/p-5qtbcu]

[28]
Rösch, F.; Herzog, H.; Qaim, S. The beginning and development of the theranostic approach in nuclear medicine, as exemplified by the radionuclide pair 86Y and 90Y. Pharmaceuticals.,  2017, 10(4), 56.
 [http://dx.doi.org/10.3390/ph10020056] [PMID: 28632200]

[29]
Poty, S.; Francesconi, L.C.; McDevitt, M.R.; Morris, M.J.; Lewis, J.S. α-Emitters for radiotherapy: From basic radiochemistry to clinical studies—part 1. J. Nucl. Med.,  2018, 59(6), 878-884.
 [http://dx.doi.org/10.2967/jnumed.116.186338] [PMID: 29545378]

[30]
Nelson, B.J.B.; Andersson, J.D.; Wuest, F. Targeted alpha therapy: Progress in radionuclide production, radiochemistry, and applications. Pharmaceutics.,  2020, 13(1), 49.
 [http://dx.doi.org/10.3390/pharmaceutics13010049] [PMID: 33396374]

[31]
Bruland, O.; Jonasdottir, T.; Fisher, D.; Larsen, R. Radium-223: From radiochemical development to clinical applications in targeted cancer therapy. Curr. Radiopharm.,  2008, 1(3), 203-208.
 [http://dx.doi.org/10.2174/1874471010801030203]

[32]
Hockley, B.G.; Scott, P.J.H. An automated method for preparation of [18F]sodium fluoride for injection, USP to address the technetium-99m isotope shortage. Appl. Radiat. Isot.,  2010, 68(1), 117-119.
 [http://dx.doi.org/10.1016/j.apradiso.2009.08.012] [PMID: 19762249]

[33]
Letellier, A.; Johnson, A.C.; Kit, N.H.; Savigny, J.F.; Batalla, A.; Parienti, J.J.; Aide, N. Uptake of radium-223 dichloride and early [18F]NaF PET response are driven by baseline [18F]NaF parameters: A pilot study in castration-resistant prostate cancer patients. Mol. Imaging Biol.,  2018, 20(3), 482-491.
 [http://dx.doi.org/10.1007/s11307-017-1132-4] [PMID: 29027074]

[34]
Mínguez, P.; Rodeño, E.; Genollá, J.; Domínguez, M.; Expósito, A.; Sjögreen Gleisner, K. Analysis of activity uptake, effective half-life and time-integrated activity for low- and high-risk papillary thyroid cancer patients treated with 1.11 GBq and 3.7 GBq of 131I-NaI respectively. Phys. Med.,  2019, 65, 143-149.
 [http://dx.doi.org/10.1016/j.ejmp.2019.08.017] [PMID: 31473501]

[35]
Vermeulen, K.; Vandamme, M.; Bormans, G.; Cleeren, F. Design and Challenges of Radiopharmaceuticals. In: Seminars in nuclear medicine; WB Saunders, 2019; Vol. 49, pp. 339-356.

[36]
Sanad, M.H.; Marzook, E.A.; El-Kawy, O.A. Radiochemical and biological characterization of 99mTc-oxiracetam as a model for brain imaging. Radiochemistry.,  2017, 59(6), 624-629.
 [http://dx.doi.org/10.1134/S1066362217060011X]

[37]
Uccelli, L.; Martini, P.; Pasquali, M.; Boschi, A. Radiochemical purity and stability of 99mTc-HMPAO in routine preparations. J. Radioanal. Nucl. Chem.,  2017, 314(2), 1177-1181.
 [http://dx.doi.org/10.1007/s10967-017-5437-1]

[38]
de Menezes, F.D.; dos Reis, S.R.R.; Pinto, S.R.; Portilho, F.L.; do Vale Chaves e Mello, F.; Helal-Neto, E.; da Silva de Barros, A.O.; Alencar, L.M.R.; de Menezes, A.S.; dos Santos, C.C.; Saraiva-Souza, A.; Perini, J.A.; Machado, D.E.; Felzenswalb, I.; Araujo-Lima, C.F.; Sukhanova, A.; Nabiev, I.; Santos-Oliveira, R. Graphene quantum dots unraveling: Green synthesis, characterization, radiolabeling with 99mTc, in vivo behavior and mutagenicity. Mater. Sci. Eng. C,  2019, 102, 405-414.
 [http://dx.doi.org/10.1016/j.msec.2019.04.058]

[39]
Costa, B.; Ilem-Özdemir, D.; Santos-Oliveira, R. Technetium-99m metastable radiochemistry for pharmaceutical applications: Old chemistry for new products. J. Coord. Chem.,  2019, 72(11), 1759-1784.
 [http://dx.doi.org/10.1080/00958972.2019.1632838]

[40]
Liu, S. Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides. Adv. Drug Deliv. Rev.,  2008, 60(12), 1347-1370.
 [http://dx.doi.org/10.1016/j.addr.2008.04.006] [PMID: 18538888]

[41]
Banerjee, S.; Pillai, M.R.A.; Knapp, F.F.R. Lutetium-177 therapeutic radiopharmaceuticals: linking chemistry, radiochemistry, and practical applications. Chem. Rev.,  2015, 115(8), 2934-2974.
 [http://dx.doi.org/10.1021/cr500171e] [PMID: 25865818]

[42]
Spang, P.; Herrmann, C.; Roesch, F. Bifunctional gallium-68 chelators: Past, present, and future. Semin. Nucl. Med.,  2016, 46(5), 373-394.
 [http://dx.doi.org/10.1053/j.semnuclmed.2016.04.003] [PMID: 27553464]

[43]
Duatti, A. Review on 99mTc radiopharmaceuticals with emphasis on new advancements. Nucl. Med. Biol.,  2021, 92, 202-216.
 [http://dx.doi.org/10.1016/j.nucmedbio.2020.05.005] [PMID: 32475681]

[44]
Eder, M.; Schäfer, M.; Bauder-Wüst, U.; Hull, W.E.; Wängler, C.; Mier, W.; Haberkorn, U.; Eisenhut, M. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging. Bioconjug. Chem.,  2012, 23(4), 688-697.
 [http://dx.doi.org/10.1021/bc200279b] [PMID: 22369515]

[45]
Benešová, M.; Schäfer, M.; Bauder-Wüst, U.; Afshar-Oromieh, A.; Kratochwil, C.; Mier, W.; Haberkorn, U.; Kopka, K.; Eder, M. Preclinical evaluation of a tailor-made DOTA-conjugated PSMA inhibitor with optimized linker moiety for imaging and endoradiotherapy of prostate cancer. J. Nucl. Med.,  2015, 56(6), 914-920.
 [http://dx.doi.org/10.2967/jnumed.114.147413] [PMID: 25883127]

[46]
Robu, S.; Schottelius, M.; Eiber, M.; Maurer, T.; Gschwend, J.; Schwaiger, M.; Wester, H.J. Preclinical evaluation and first patient application of 99m Tc-PSMA-I&S for SPECT imaging and radioguided surgery in prostate cancer. J. Nucl. Med.,  2017, 58(2), 235-242.
 [http://dx.doi.org/10.2967/jnumed.116.178939] [PMID: 27635024]

[47]
Lindner, T.; Loktev, A.; Altmann, A.; Giesel, F.; Kratochwil, C.; Debus, J.; Jäger, D.; Mier, W.; Haberkorn, U. Development of quinoline-based theranostic ligands for the targeting of fibroblast activation protein. J. Nucl. Med.,  2018, 59(9), 1415-1422.
 [http://dx.doi.org/10.2967/jnumed.118.210443] [PMID: 29626119]

[48]
Loktev, A.; Lindner, T.; Burger, E.M.; Altmann, A.; Giesel, F.; Kratochwil, C.; Debus, J.; Marmé, F.; Jäger, D.; Mier, W.; Haberkorn, U. Development of fibroblast activation protein–targeted radiotracers with improved tumor retention. J. Nucl. Med.,  2019, 60(10), 1421-1429.
 [http://dx.doi.org/10.2967/jnumed.118.224469] [PMID: 30850501]

[49]
Lindner, T.; Altmann, A.; Krämer, S.; Kleist, C.; Loktev, A.; Kratochwil, C.; Giesel, F.; Mier, W.; Marme, F.; Debus, J.; Haberkorn, U. Design and development of 99m Tc-Labeled FAPI tracers for SPECT imaging and 188 Re therapy. J. Nucl. Med.,  2020, 61(10), 1507-1513.
 [http://dx.doi.org/10.2967/jnumed.119.239731] [PMID: 32169911]

[50]
Fersing, C.; Bouhlel, A.; Cantelli, C.; Garrigue, P.; Lisowski, V.; Guillet, B. A comprehensive review of non-covalent radiofluorination approaches using aluminum [18F]fluoride: Will [18F]AlF Replace 68Ga for metal chelate labeling? Molecules,  2019, 24(16), 2866.
 [http://dx.doi.org/10.3390/molecules24162866] [PMID: 31394799]

[51]
Lindner, T.; Altmann, A.; Giesel, F.; Kratochwil, C.; Kleist, C.; Krämer, S.; Mier, W.; Cardinale, J.; Kauczor, H.U.; Jäger, D.; Debus, J.; Haberkorn, U. 18F-labeled tracers targeting fibroblast activation protein. EJNMMI Radiopharm. Chem.,  2021, 6(1), 26.
 [http://dx.doi.org/10.1186/s41181-021-00144-x] [PMID: 34417894]

[52]
Wang, H.; Guo, X.; Jiang, S.; Tang, G. Automated synthesis of [18F]Florbetaben as Alzheimer’s disease imaging agent based on a synthesis module system. Appl. Radiat. Isot.,  2013, 71(1), 41-46.
 [http://dx.doi.org/10.1016/j.apradiso.2012.09.014] [PMID: 23085550]

[53]
Zhang, L.; Zhang, A.; Yao, X.; Zhang, Y.; Liu, F.; Hong, H.; Zha, Z.; Liu, Y.; Wu, Z.; Qiao, J.; Zhu, L.; Kung, H.F. An improved preparation of [ 18 F]AV-45 by simplified solid-phase extraction purification. J. Labelled Comp. Radiopharm.,  2020, 63(3), 108-118.
 [http://dx.doi.org/10.1002/jlcr.3813] [PMID: 31697847]

[54]
Mossine, A.V.; Brooks, A.F.; Henderson, B.D.; Hockley, B.G.; Frey, K.A.; Scott, P.J.H. An updated radiosynthesis of [18F]AV1451 for tau PET imaging. EJNMMI Radiopharm. Chem.,  2017, 2(1), 7.
 [http://dx.doi.org/10.1186/s41181-017-0027-7] [PMID: 29503848]

[55]
Kung, M.P.; Hou, C.; Zhuang, Z.P.; Zhang, B.; Skovronsky, D.; Trojanowski, J.Q.; Lee, V.M.Y.; Kung, H.F. IMPY: An improved thioflavin-T derivative for in vivo labeling of β-amyloid plaques. Brain Res.,  2002, 956(2), 202-210.
 [http://dx.doi.org/10.1016/S0006-8993(02)03436-4] [PMID: 12445687]

[56]
Goud, N.S.; Bhattacharya, A.; Joshi, R.K.; Nagaraj, C.; Bharath, R.D.; Kumar, P. Carbon-11: Radiochemistry and target-based PET molecular imaging applications in oncology, cardiology, and neurology. J. Med. Chem.,  2021, 64(3), 1223-1259.
 [http://dx.doi.org/10.1021/acs.jmedchem.0c01053] [PMID: 33499603]

[57]
Schirrmacher, R.; Wängler, B.; Bailey, J.; Bernard-Gauthier, V. Small prosthetic groups in 18f-radiochemistry: Useful auxiliaries for the design of 18F-PET tracers. In: Seminars in nuclear medicine; WB Saunders, 2017; Vol. 47, pp. 474-492.

[58]
Navarro, L.; Berdal, M.; Chérel, M.; Pecorari, F.; Gestin, J.F.; Guérard, F. Prosthetic groups for radioiodination and astatination of peptides and proteins: A comparative study of five potential bioorthogonal labeling strategies. Bioorg. Med. Chem.,  2019, 27(1), 167-174.
 [http://dx.doi.org/10.1016/j.bmc.2018.11.034] [PMID: 30529152]

[59]
Goud, N.S.; Joshi, R.K.; Bharath, R.D.; Kumar, P. Fluorine-18: A radionuclide with diverse range of radiochemistry and synthesis strategies for target based PET diagnosis. Eur. J. Med. Chem.,  2020, 187, 111979.
 [http://dx.doi.org/10.1016/j.ejmech.2019.111979] [PMID: 31877537]

[60]
Olberg, D.E.; Arukwe, J.M.; Grace, D.; Hjelstuen, O.K.; Solbakken, M.; Kindberg, G.M.; Cuthbertson, A. One step radiosynthesis of 6-[(18)F]fluoronicotinic acid 2,3,5,6-tetrafluorophenyl ester ([(18)F]F-Py-TFP): A new prosthetic group for efficient labeling of biomolecules with fluorine-18. J. Med. Chem.,  2010, 53(4), 1732-1740.
 [http://dx.doi.org/10.1021/jm9015813] [PMID: 20088512]

[61]
Cardinale, J.; Schäfer, M.; Benešová, M.; Bauder-Wüst, U.; Leotta, K.; Eder, M.; Neels, O.C.; Haberkorn, U.; Giesel, F.L.; Kopka, K. Preclinical evaluation of 18 F-PSMA-1007, a new prostate-specific membrane antigen ligand for prostate cancer imaging. J. Nucl. Med.,  2017, 58(3), 425-431.
 [http://dx.doi.org/10.2967/jnumed.116.181768] [PMID: 27789722]

[62]
Coliva, A.; Monterisi, C.; Apollaro, A.; Gatti, D.; Penso, M.; Gianolli, L.; Perani, D.; Gilardi, M.C.; Carpinelli, A. Synthesis optimization of 2-(4-N-[11C]methylaminophenyl)-6-hydroxybenzothiazole ([11C]PIB), β-amyloid PET imaging tracer for Alzheimer’s disease diagnosis. Appl. Radiat. Isot.,  2015, 105, 66-71.
 [http://dx.doi.org/10.1016/j.apradiso.2015.07.003] [PMID: 26248085]

[63]
Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin.,  2022, 72(1), 7-33.
 [http://dx.doi.org/10.3322/caac.21708] [PMID: 35020204]

[64]
Davis, M.I.; Bennett, M.J.; Thomas, L.M.; Bjorkman, P.J. Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase. Proc. Natl. Acad. Sci. USA,  2005, 102(17), 5981-5986.
 [http://dx.doi.org/10.1073/pnas.0502101102] [PMID: 15837926]

[65]
Ristau, B.T.; O’Keefe, D.S.; Bacich, D.J. The prostate-specific membrane antigen: Lessons and current clinical implications from 20 years of research. Urol. Oncol.,  2014, 32(3), 272-279.
 [http://dx.doi.org/10.1016/j.urolonc.2013.09.003] [PMID: 24321253]

[66]
Perner, S.; Hofer, M.D.; Kim, R.; Shah, R.B.; Li, H.; Möller, P.; Hautmann, R.E.; Gschwend, J.E.; Kuefer, R.; Rubin, M.A. Prostate-specific membrane antigen expression as a predictor of prostate cancer progression. Hum. Pathol.,  2007, 38(5), 696-701.
 [http://dx.doi.org/10.1016/j.humpath.2006.11.012] [PMID: 17320151]

[67]
Minner, S.; Wittmer, C.; Graefen, M.; Salomon, G.; Steuber, T.; Haese, A.; Huland, H.; Bokemeyer, C.; Yekebas, E.; Dierlamm, J.; Balabanov, S.; Kilic, E.; Wilczak, W.; Simon, R.; Sauter, G.; Schlomm, T. High level PSMA expression is associated with early psa recurrence in surgically treated prostate cancer. Prostate,  2011, 71(3), 281-288.
 [http://dx.doi.org/10.1002/pros.21241] [PMID: 20809553]

[68]
Sweat, S.D.; Pacelli, A.; Murphy, G.P.; Bostwick, D.G. Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases. Urology,  1998, 52(4), 637-640.
 [http://dx.doi.org/10.1016/S0090-4295(98)00278-7] [PMID: 9763084]

[69]
Gorges, T.M.; Riethdorf, S.; von Ahsen, O.; Nastały, P.; Röck, K.; Boede, M.; Peine, S.; Kuske, A.; Schmid, E.; Kneip, C.; König, F.; Rudolph, M.; Pantel, K. Heterogeneous PSMA expression on circulating tumor cells - a potential basis for stratification and monitoring of PSMA-directed therapies in prostate cancer. Oncotarget.,  2016, 7(23), 34930-34941.
 [http://dx.doi.org/10.18632/oncotarget.9004] [PMID: 27145459]

[70]
Chang, S.S.; Reuter, V.E.; Heston, W.D.W.; Bander, N.H.; Grauer, L.S.; Gaudin, P.B. Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res.,  1999, 59(13), 3192-3198.
 [PMID: 10397265]

[71]
Nomura, N.; Pastorino, S.; Jiang, P.; Lambert, G.; Crawford, J.R.; Gymnopoulos, M.; Piccioni, D.; Juarez, T.; Pingle, S.C.; Makale, M.; Kesari, S. Prostate specific membrane antigen (PSMA) expression in primary gliomas and breast cancer brain metastases. Cancer Cell Int.,  2014, 14(1), 26.
 [http://dx.doi.org/10.1186/1475-2867-14-26] [PMID: 24645697]

[72]
O’Keefe, D.S.; Bacich, D.J.; Huang, S.S.; Heston, W.D.W. A perspective on the evolving story of PSMA biology, PSMA-based imaging, and endoradiotherapeutic strategies. J. Nucl. Med.,  2018, 59(7), 1007-1013.
 [http://dx.doi.org/10.2967/jnumed.117.203877] [PMID: 29674422]

[73]
Horoszewicz, J.S.; Leong, S.S.; Kawinski, E.; Karr, J.P.; Rosenthal, H.; Chu, T.M.; Mirand, E.A.; Murphy, G.P. LNCaP model of human prostatic carcinoma. Cancer Res.,  1983, 43(4), 1809-1818.
 [PMID: 6831420]

[74]
Israeli, R.S.; Powell, C.T.; Fair, W.R.; Heston, W.D.W. Molecular cloning of a complementary DNA encoding a prostate-specific membrane antigen. Cancer Res.,  1993, 53(2), 227-230.
 [PMID: 8417812]

[75]
Kozikowski, A.P.; Nan, F.; Conti, P.; Zhang, J.; Ramadan, E.; Bzdega, T.; Wroblewska, B.; Neale, J.H.; Pshenichkin, S.; Wroblewski, J.T. Design of remarkably simple, yet potent urea-based inhibitors of glutamate carboxypeptidase II (NAALADase). J. Med. Chem.,  2001, 44(3), 298-301.
 [http://dx.doi.org/10.1021/jm000406m] [PMID: 11462970]

[76]
Weineisen, M.; Simecek, J.; Schottelius, M.; Schwaiger, M.; Wester, H.J. Synthesis and preclinical evaluation of DOTAGA-conjugated PSMA ligands for functional imaging and endoradiotherapy of prostate cancer. EJNMMI Res.,  2014, 4(1), 63.
 [http://dx.doi.org/10.1186/s13550-014-0063-1] [PMID: 26116124]

[77]
Weineisen, M.; Schottelius, M.; Simecek, J.; Baum, R.P.; Yildiz, A.; Beykan, S.; Kulkarni, H.R.; Lassmann, M.; Klette, I.; Eiber, M.; Schwaiger, M.; Wester, H.J. 68 Ga- and 177 Lu-Labeled PSMA I&T: Optimization of a PSMA-targeted theranostic concept and first proof-of-concept human studies. J. Nucl. Med.,  2015, 56(8), 1169-1176.
 [http://dx.doi.org/10.2967/jnumed.115.158550] [PMID: 26089548]

[78]
Benešová, M.; Bauder-Wüst, U.; Schäfer, M.; Klika, K.D.; Mier, W.; Haberkorn, U.; Kopka, K.; Eder, M. Linker modification strategies to control the prostate-specific membrane antigen (PSMA)-targeting and pharmacokinetic properties of DOTA-conjugated PSMA inhibitors. J. Med. Chem.,  2016, 59(5), 1761-1775.
 [http://dx.doi.org/10.1021/acs.jmedchem.5b01210] [PMID: 26878194]

[79]
Robu, S.; Schmidt, A.; Eiber, M.; Schottelius, M.; Günther, T.; Hooshyar Yousefi, B.; Schwaiger, M.; Wester, H.J. Synthesis and preclinical evaluation of novel 18F-labeled Glu-urea-Glu-based PSMA inhibitors for prostate cancer imaging: A comparison with 18F-DCFPyl and 18F-PSMA-1007. EJNMMI Res.,  2018, 8(1), 30.
 [http://dx.doi.org/10.1186/s13550-018-0382-8] [PMID: 29651565]

[80]
Mease, R.C.; Dusich, C.L.; Foss, C.A.; Ravert, H.T.; Dannals, R.F.; Seidel, J.; Prideaux, A.; Fox, J.J.; Sgouros, G.; Kozikowski, A.P.; Pomper, M.G. N-[N-[(S)-1,3-Dicarboxypropyl]carbamoyl]-4-[18F]fluorobenzyl-L-cysteine, [18F]DCFBC: A new imaging probe for prostate cancer. Clin. Cancer Res.,  2008, 14(10), 3036-3043.
 [http://dx.doi.org/10.1158/1078-0432.CCR-07-1517] [PMID: 18483369]

[81]
Cho, S.Y.; Gage, K.L.; Mease, R.C.; Senthamizhchelvan, S.; Holt, D.P.; Jeffrey-Kwanisai, A.; Endres, C.J.; Dannals, R.F.; Sgouros, G.; Lodge, M.; Eisenberger, M.A.; Rodriguez, R.; Carducci, M.A.; Rojas, C.; Slusher, B.S.; Kozikowski, A.P.; Pomper, M.G. Biodistribution, tumor detection, and radiation dosimetry of 18F-DCFBC, a low-molecular-weight inhibitor of prostate-specific membrane antigen, in patients with metastatic prostate cancer. J. Nucl. Med.,  2012, 53(12), 1883-1891.
 [http://dx.doi.org/10.2967/jnumed.112.104661] [PMID: 23203246]

[82]
Rowe, S.P.; Gage, K.L.; Faraj, S.F.; Macura, K.J.; Cornish, T.C.; Gonzalez-Roibon, N.; Guner, G.; Munari, E.; Partin, A.W.; Pavlovich, C.P.; Han, M.; Carter, H.B.; Bivalacqua, T.J.; Blackford, A.; Holt, D.; Dannals, R.F.; Netto, G.J.; Lodge, M.A.; Mease, R.C.; Pomper, M.G.; Cho, S.Y. 18 F-DCFBC PET/CT for PSMA-based detection and characterization of primary prostate cancer. J. Nucl. Med.,  2015, 56(7), 1003-1010.
 [http://dx.doi.org/10.2967/jnumed.115.154336] [PMID: 26069305]

[83]
Rowe, S.P.; Macura, K.J.; Ciarallo, A.; Mena, E.; Blackford, A.; Nadal, R.; Antonarakis, E.S.; Eisenberger, M.A.; Carducci, M.A.; Ross, A.E.; Kantoff, P.W.; Holt, D.P.; Dannals, R.F.; Mease, R.C.; Pomper, M.G.; Cho, S.Y. Comparison of prostate-specific membrane antigen–based 18 F-DCFBC PET/CT to conventional imaging modalities for detection of hormone-naïve and castration-resistant metastatic prostate cancer. J. Nucl. Med.,  2016, 57(1), 46-53.
 [http://dx.doi.org/10.2967/jnumed.115.163782] [PMID: 26493203]

[84]
Chen, Y.; Pullambhatla, M.; Foss, C.A.; Byun, Y.; Nimmagadda, S.; Senthamizhchelvan, S.; Sgouros, G.; Mease, R.C.; Pomper, M.G. 2-(3-1-Carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl-ureido)-pentanedioic acid, [18F]DCFPyL, a PSMA-based PET imaging agent for prostate cancer. Clin. Cancer Res.,  2011, 17(24), 7645-7653.
 [http://dx.doi.org/10.1158/1078-0432.CCR-11-1357] [PMID: 22042970]

[85]
Bouvet, V.; Wuest, M.; Jans, H.S.; Janzen, N.; Genady, A.R.; Valliant, J.F.; Benard, F.; Wuest, F. Automated synthesis of [18F]DCFPyL via direct radiofluorination and validation in preclinical prostate cancer models. EJNMMI Res.,  2016, 6(1), 40.
 [http://dx.doi.org/10.1186/s13550-016-0195-6] [PMID: 27142881]

[86]
Pan, K.H.; Wang, J.F.; Wang, C.Y.; Nikzad, A.A.; Kong, F.Q.; Jian, L.; Zhang, Y.Q.; Lu, X.M.; Xu, B.; Wang, Y.L.; Chen, M. Evaluation of 18F-DCFPyL PSMA PET/CT for prostate cancer: A meta-analysis. Front. Oncol.,  2021, 10, 597422.
 [http://dx.doi.org/10.3389/fonc.2020.597422] [PMID: 33680924]

[87]
Metser, U.; Zukotynski, K.; Mak, V.; Langer, D.; MacCrostie, P.; Finelli, A.; Kapoor, A.; Chin, J.; Lavallée, L.; Klotz, L.H.; Hagerty, M.; Hildebrand, C.; Bauman, G. Effect of 18 F-DCFPyL PET/CT on the management of patients with recurrent prostate cancer: Results of a prospective multicenter registry trial. Radiology,  2022, 303(2), 414-422.
 [http://dx.doi.org/10.1148/radiol.211824] [PMID: 35076300]

[88]
U.S. Food and Drug Administration (FDA).  FDA approves second PSMA-targeted PET imaging drug for men with prostate cancer. Available from: https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-second-psma-targeted-pet-imaging-drug-men-prostate-cancer (Accessed on: May 24, 2023).

[89]
Zechmann, C.M.; Afshar-Oromieh, A.; Armor, T.; Stubbs, J.B.; Mier, W.; Hadaschik, B.; Joyal, J.; Kopka, K.; Debus, J.; Babich, J.W.; Haberkorn, U. Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy. Eur. J. Nucl. Med. Mol. Imaging,  2014, 41(7), 1280-1292.
 [http://dx.doi.org/10.1007/s00259-014-2713-y] [PMID: 24577951]

[90]
Study of I-131-1095 radiotherapy in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer who are chemotherapy naive and have progressed on abiraterone. Patent NCT03939689, 2023.

[91]
Rajasekaran, S.A.; Anilkumar, G.; Oshima, E.; Bowie, J.U.; Liu, H.; Heston, W.; Bander, N.H.; Rajasekaran, A.K. A novel cytoplasmic tail MXXXL motif mediates the internalization of prostate-specific membrane antigen. Mol. Biol. Cell,  2003, 14(12), 4835-4845.
 [http://dx.doi.org/10.1091/mbc.e02-11-0731] [PMID: 14528023]

[92]
Liu, T.; Toriyabe, Y.; Kazak, M.; Berkman, C.E. Pseudoirreversible inhibition of prostate-specific membrane antigen by phosphoramidate peptidomimetics. Biochemistry,  2008, 47(48), 12658-12660.
 [http://dx.doi.org/10.1021/bi801883v] [PMID: 18983168]

[93]
Afshar-Oromieh, A.; Haberkorn, U.; Eder, M.; Eisenhut, M.; Zechmann, C.M. [68Ga]Gallium-labelled PSMA ligand as superior PET tracer for the diagnosis of prostate cancer: comparison with 18F-FECH. Eur. J. Nucl. Med. Mol. Imaging,  2012, 39(6), 1085-1086.
 [http://dx.doi.org/10.1007/s00259-012-2069-0] [PMID: 22310854]

[94]
Hope, T.A.; Aggarwal, R.; Chee, B.; Tao, D.; Greene, K.L.; Cooperberg, M.R.; Feng, F.; Chang, A.; Ryan, C.J.; Small, E.J.; Carroll, P.R. Impact of 68 Ga-PSMA-11 PET on management in patients with biochemically recurrent prostate cancer. J. Nucl. Med.,  2017, 58(12), 1956-1961.
 [http://dx.doi.org/10.2967/jnumed.117.192476] [PMID: 28522741]

[95]
Calais, J.; Czernin, J.; Cao, M.; Kishan, A.U.; Hegde, J.V.; Shaverdian, N.; Sandler, K.; Chu, F.I.; King, C.R.; Steinberg, M.L.; Rauscher, I.; Schmidt-Hegemann, N.S.; Poeppel, T.; Hetkamp, P.; Ceci, F.; Herrmann, K.; Fendler, W.P.; Eiber, M.; Nickols, N.G. 68 Ga-PSMA-11 PET/CT mapping of prostate cancer biochemical recurrence after radical prostatectomy in 270 patients with a PSA level of less than 1.0 ng/mL: Impact on salvage radiotherapy planning. J. Nucl. Med.,  2018, 59(2), 230-237.
 [http://dx.doi.org/10.2967/jnumed.117.201749] [PMID: 29123013]

[96]
Cardinal Health. 2021. FDA-Approved Radiopharmaceuticals. Available from: https://www.cardinalhealth.com/content/dam/corp/web/documents/fact-sheet/cardinal-health-fda-approved-radiopharmaceuticals.pdf

[97]
Eder, M.; Wängler, B.; Knackmuss, S.; LeGall, F.; Little, M.; Haberkorn, U.; Mier, W.; Eisenhut, M. Tetrafluorophenolate of HBED-CC: A versatile conjugation agent for 68Ga-labeled small recombinant antibodies. Eur. J. Nucl. Med. Mol. Imaging,  2008, 35(10), 1878-1886.
 [http://dx.doi.org/10.1007/s00259-008-0816-z] [PMID: 18509635]

[98]
Bräuer, A.; Grubert, L.S.; Roll, W.; Schrader, A.J.; Schäfers, M.; Bögemann, M.; Rahbar, K. 177Lu-PSMA-617 radioligand therapy and outcome in patients with metastasized castration-resistant prostate cancer. Eur. J. Nucl. Med. Mol. Imaging,  2017, 44(10), 1663-1670.
 [http://dx.doi.org/10.1007/s00259-017-3751-z] [PMID: 28624848]

[99]
Hofman, M.S.; Violet, J.; Hicks, R.J.; Ferdinandus, J.; Thang, S.P.; Akhurst, T.; Iravani, A.; Kong, G.; Ravi Kumar, A.; Murphy, D.G.; Eu, P.; Jackson, P.; Scalzo, M.; Williams, S.G.; Sandhu, S. [ 177 Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): A single-centre, single-arm, phase 2 study. Lancet Oncol.,  2018, 19(6), 825-833.
 [http://dx.doi.org/10.1016/S1470-2045(18)30198-0] [PMID: 29752180]

[100]
Yadav, M.P.; Ballal, S.; Bal, C.; Sahoo, R.K.; Damle, N.A.; Tripathi, M.; Seth, A. Efficacy and safety of 177Lu-PSMA-617 radioligand therapy in metastatic castration-resistant prostate cancer patients. Clin. Nucl. Med.,  2020, 45(1), 19-31.
 [http://dx.doi.org/10.1097/RLU.0000000000002833] [PMID: 31789908]

[101]
FDA. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA approves Pluvicto for metastatic castration-resistant prostate cancer.,  Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer (Accessed on: May 24, 2022).

[102]
Kratochwil, C.; Bruchertseifer, F.; Giesel, F.L.; Weis, M.; Verburg, F.A.; Mottaghy, F.; Kopka, K.; Apostolidis, C.; Haberkorn, U.; Morgenstern, A. 225 Ac-PSMA-617 for PSMA-targeted α-radiation therapy of metastatic castration-resistant prostate cancer. J. Nucl. Med.,  2016, 57(12), 1941-1944.
 [http://dx.doi.org/10.2967/jnumed.116.178673] [PMID: 27390158]

[103]
Ma, J.; Li, L.; Liao, T.; Gong, W.; Zhang, C. Efficacy and safety of 225Ac-PSMA-617-targeted alpha therapy in metastatic castration-resistant prostate cancer: A systematic review and meta-analysis. Front. Oncol.,  2022, 12, 796657.
 [http://dx.doi.org/10.3389/fonc.2022.796657] [PMID: 35186737]

[104]
Study of 225Ac-PSMA-617 in men with PSMA-positive prostate cancer. Patent NCT04597411, 2022.

[105]
Wang, Z.; Tian, R.; Niu, G.; Ma, Y.; Lang, L.; Szajek, L.P.; Kiesewetter, D.O.; Jacobson, O.; Chen, X. Single low-dose injection of evans blue modified PSMA-617 radioligand therapy eliminates prostate-specific membrane antigen positive tumors. Bioconjug. Chem.,  2018, 29(9), 3213-3221.
 [http://dx.doi.org/10.1021/acs.bioconjchem.8b00556] [PMID: 30105912]

[106]
Zang, J.; Fan, X.; Wang, H.; Liu, Q.; Wang, J.; Li, H.; Li, F.; Jacobson, O.; Niu, G.; Zhu, Z.; Chen, X. First-in-human study of 177Lu-EB-PSMA-617 in patients with metastatic castration-resistant prostate cancer. Eur. J. Nucl. Med. Mol. Imaging,  2019, 46(1), 148-158.
 [http://dx.doi.org/10.1007/s00259-018-4096-y] [PMID: 30090965]

[107]
Zang, J.; Liu, Q.; Sui, H.; Wang, R.; Jacobson, O.; Fan, X.; Zhu, Z.; Chen, X. 177 Lu-EB-PSMA radioligand therapy with escalating doses in patients with metastatic castration-resistant prostate cancer. J. Nucl. Med.,  2020, 61(12), 1772-1778.
 [http://dx.doi.org/10.2967/jnumed.120.242263] [PMID: 32358086]

[108]
Therapeutic efficiency and response to 2.0 GBq (54mCi)177Lu-EB-PSMA-617 in patients with mCRPC. Patent NCT04996602, 2022.

[109]
Lu177-EB-PSMA617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer. Patent NCT03780075, 2022.

[110]
Kuo, H.T.; Merkens, H.; Zhang, Z.; Uribe, C.F.; Lau, J.; Zhang, C.; Colpo, N.; Lin, K.S.; Bénard, F. Enhancing treatment efficacy of 177 Lu-PSMA-617 with the conjugation of an albumin-binding motif: Preclinical dosimetry and endoradiotherapy studies. Mol. Pharm.,  2018, 15(11), 5183-5191.
 [http://dx.doi.org/10.1021/acs.molpharmaceut.8b00720] [PMID: 30251544]

[111]
Kuo, H.T.; Lin, K.S.; Zhang, Z.; Uribe, C.F.; Merkens, H.; Zhang, C.; Bénard, F. 177 Lu-labeled albumin-binder–conjugated PSMA-targeting agents with extremely high tumor uptake and enhanced tumor-to-kidney absorbed dose ratio. J. Nucl. Med.,  2021, 62(4), 521-527.
 [http://dx.doi.org/10.2967/jnumed.120.250738] [PMID: 32859704]

[112]
Schmuck, S.; Mamach, M.; Wilke, F.; von Klot, C.A.; Henkenberens, C.; Thackeray, J.T.; Sohns, J.M.; Geworski, L.; Ross, T.L.; Wester, H.J.; Christiansen, H.; Bengel, F.M.; Derlin, T. Multiple time-point 68Ga-PSMA I&T PET/CT for characterization of primary prostate cancer. Clin. Nucl. Med.,  2017, 42(6), e286-e293.
 [http://dx.doi.org/10.1097/RLU.0000000000001589] [PMID: 28221194]

[113]
Berliner, C.; Tienken, M.; Frenzel, T.; Kobayashi, Y.; Helberg, A.; Kirchner, U.; Klutmann, S.; Beyersdorff, D.; Budäus, L.; Wester, H.J.; Mester, J.; Bannas, P. Detection rate of PET/CT in patients with biochemical relapse of prostate cancer using [68Ga]PSMA I&T and comparison with published data of [68Ga]PSMA HBED-CC. Eur. J. Nucl. Med. Mol. Imaging,  2017, 44(4), 670-677.
 [http://dx.doi.org/10.1007/s00259-016-3572-5] [PMID: 27896369]

[114]
Heck, M.M.; Tauber, R.; Schwaiger, S.; Retz, M.; D’Alessandria, C.; Maurer, T.; Gafita, A.; Wester, H.J.; Gschwend, J.E.; Weber, W.A.; Schwaiger, M.; Knorr, K.; Eiber, M. Treatment outcome, toxicity, and predictive factors for radioligand therapy with 177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer. Eur. Urol.,  2019, 75(6), 920-926.
 [http://dx.doi.org/10.1016/j.eururo.2018.11.016] [PMID: 30473431]

[115]
Schuchardt, C.; Zhang, J.; Kulkarni, H.R.; Chen, X.; Mueller, D.; Baum, R.P. Prostate-specific membrane antigen radioligand therapy using 177 Lu-PSMA I&T and 177 Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer: Comparison of safety, biodistribution and dosimetry. J. Nucl. Med.,  2021, 63(8), 1199-1207.

[116]
225Ac-J591 Plus 177Lu-PSMA-I&T for mCRPC. Patent NCT04886986, 2022.

[117]
Tagawa, S.T.; Sun, M.; Sartor, A.O.; Thomas, C.; Singh, S.; Bissassar, M.; Fernandez, E.; Niaz, M.J.; Ho, B.; Vallabhajosula, S.; Babich, J.; Molina, A.M.; Sternberg, C.N.; Nanus, D.M.; Osborne, J.; Bander, N.H.; Phase, I. Phase I study of 225 Ac-J591 for men with metastatic castration-resistant prostate cancer (mCRPC). J. Clin. Oncol.,  2021, 39(15_suppl), 5015-5015.
 [http://dx.doi.org/10.1200/JCO.2021.39.15_suppl.5015]

[118]
Schmidt, A.; Wirtz, M.; Färber, S.F.; Osl, T.; Beck, R.; Schottelius, M.; Schwaiger, M.; Wester, H.J. Effect of carbohydration on the theranostic tracer PSMA I&T. ACS Omega,  2018, 3(7), 8278-8287.
 [http://dx.doi.org/10.1021/acsomega.8b00790] [PMID: 30087939]

[119]
Giesel, F.L.; Cardinale, J.; Schäfer, M.; Neels, O.; Benešová, M.; Mier, W.; Haberkorn, U.; Kopka, K.; Kratochwil, C. 18F-Labelled PSMA-1007 shows similarity in structure, biodistribution and tumour uptake to the theragnostic compound PSMA-617. Eur. J. Nucl. Med. Mol. Imaging,  2016, 43(10), 1929-1930.
 [http://dx.doi.org/10.1007/s00259-016-3447-9] [PMID: 27342416]

[120]
Giesel, F.L.; Hadaschik, B.; Cardinale, J.; Radtke, J.; Vinsensia, M.; Lehnert, W.; Kesch, C.; Tolstov, Y.; Singer, S.; Grabe, N.; Duensing, S.; Schäfer, M.; Neels, O.C.; Mier, W.; Haberkorn, U.; Kopka, K.; Kratochwil, C. F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients. Eur. J. Nucl. Med. Mol. Imaging,  2017, 44(4), 678-688.
 [http://dx.doi.org/10.1007/s00259-016-3573-4] [PMID: 27889802]

[121]
Giesel, F.L.; Knorr, K.; Spohn, F.; Will, L.; Maurer, T.; Flechsig, P.; Neels, O.; Schiller, K.; Amaral, H.; Weber, W.A.; Haberkorn, U.; Schwaiger, M.; Kratochwil, C.; Choyke, P.; Kramer, V.; Kopka, K.; Eiber, M. Detection efficacy of 18 F-PSMA-1007 PET/CT in 251 patients with biochemical recurrence of prostate cancer after radical prostatectomy. J. Nucl. Med.,  2019, 60(3), 362-368.
 [http://dx.doi.org/10.2967/jnumed.118.212233] [PMID: 30042163]

[122]
Sachpekidis, C.; Afshar-Oromieh, A.; Kopka, K.; Strauss, D.S.; Pan, L.; Haberkorn, U.; Dimitrakopoulou-Strauss, A. 18F-PSMA-1007 multiparametric, dynamic PET/CT in biochemical relapse and progression of prostate cancer. Eur. J. Nucl. Med. Mol. Imaging,  2020, 47(3), 592-602.
 [http://dx.doi.org/10.1007/s00259-019-04569-0] [PMID: 31728588]

[123]
Efficacy of [18F]PSMA-1007 PET/CT in patients with biochemial recurrent prostate cancer. Patent NCT04742361, 2023.

[124]
Dietlein, F.; Kobe, C.; Hohberg, M.; Zlatopolskiy, B.D.; Krapf, P.; Endepols, H.; Täger, P.; Hammes, J.; Heidenreich, A.; Persigehl, T.; Neumaier, B.; Drzezga, A.; Dietlein, M. Intraindividual comparison of 18 F-PSMA-1007 with Renally excreted PSMA ligands for PSMA PET imaging in patients with relapsed prostate cancer. J. Nucl. Med.,  2020, 61(5), 729-734.
 [http://dx.doi.org/10.2967/jnumed.119.234898] [PMID: 31628219]

[125]
Kuten, J.; Dekalo, S.; Mintz, I.; Yossepowitch, O.; Mano, R.; Even-Sapir, E. The significance of equivocal bone findings in staging PSMA imaging in the preoperative setting: validation of the PSMA-RADS version 1.0. EJNMMI Res.,  2021, 11(1), 3.
 [http://dx.doi.org/10.1186/s13550-020-00745-8] [PMID: 33409930]

[126]
Wurzer, A.; Di Carlo, D.; Schmidt, A.; Beck, R.; Eiber, M.; Schwaiger, M.; Wester, H.J. Radiohybrid ligands: A novel tracer concept exemplified by 18 F- or 68 Ga-Labeled rhPSMA inhibitors. J. Nucl. Med.,  2020, 61(5), 735-742.
 [http://dx.doi.org/10.2967/jnumed.119.234922] [PMID: 31862804]

[127]
Oh, S.W.; Wurzer, A.; Teoh, E.J.; Oh, S.; Langbein, T.; Krönke, M.; Herz, M.; Kropf, S.; Wester, H.J.; Weber, W.A.; Eiber, M. Quantitative and qualitative analyses of biodistribution and PET image quality of a novel radiohybrid PSMA, 18 F-rhPSMA-7, in patients with prostate cancer. J. Nucl. Med.,  2020, 61(5), 702-709.
 [http://dx.doi.org/10.2967/jnumed.119.234609] [PMID: 31836686]

[128]
Eiber, M.; Kroenke, M.; Wurzer, A.; Ulbrich, L.; Jooß, L.; Maurer, T.; Horn, T.; Schiller, K.; Langbein, T.; Buschner, G.; Wester, H.J.; Weber, W. 18 F-rhPSMA-7 PET for the detection of biochemical recurrence of prostate cancer after radical prostatectomy. J. Nucl. Med.,  2020, 61(5), 696-701.
 [http://dx.doi.org/10.2967/jnumed.119.234914] [PMID: 31836682]

[129]
Kroenke, M.; Wurzer, A.; Schwamborn, K.; Ulbrich, L.; Jooß, L.; Maurer, T.; Horn, T.; Rauscher, I.; Haller, B.; Herz, M.; Wester, H.J.; Weber, W.A.; Eiber, M. Histologically confirmed diagnostic efficacy of 18 F-rhPSMA-7 PET for N-staging of patients with primary high-risk prostate cancer. J. Nucl. Med.,  2020, 61(5), 710-715.
 [http://dx.doi.org/10.2967/jnumed.119.234906] [PMID: 31836681]

[130]
Wurzer, A.; Parzinger, M.; Konrad, M.; Beck, R.; Günther, T.; Felber, V.; Färber, S.; Di Carlo, D.; Wester, H.J. Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: Influence of the stereoconfiguration on pharmacokinetics. EJNMMI Res.,  2020, 10(1), 149.
 [http://dx.doi.org/10.1186/s13550-020-00740-z] [PMID: 33284394]

[131]
Rauscher, I.; Karimzadeh, A.; Schiller, K.; Horn, T.; D’Alessandria, C.; Franz, C.; Wörther, H.; Nguyen, N.; Combs, S.E.; Weber, W.A.; Eiber, M. Detection efficacy of 18F-rhPSMA-7.3 PET/CT and impact on patient management in patients with biochemical recurrence of prostate cancer after radical prostatectomy and prior to potential salvage treatment. J. Nucl. Med.,  2021, 62(12), 1719-1726.
 [http://dx.doi.org/10.2967/jnumed.120.260091] [PMID: 33712531]

[132]
Jani, A.B.; Ravizzini, G.C.; Gartrell, B.A.; Siegel, B.A.; Twardowski, P.; Saltzstein, D.; Fleming, M.T.; Chau, A.; Davis, P.; Chapin, B.F.; Schuster, D.M.; Allaf, M.; Avery, R.J.; Avril, N.; Barker, H.; Belkoff, L.; Bostrom, P.; Cher, M.L.; Chisholm, D.; Covington, M.F.; Cox, I.; Esposito, G.; Gardiner, P.; Gauden, D.; Helfand, B.; Hermsen, R.; Josephson, D.; Kay, M.; Koontz, B.F.; Kostakoglu, L.; Kuo, P.; Lavely, W.; Liem, I.H.; Lokuta, M.; Lowentritt, B.; Michalski, J.; Miller, M.P.; Mourtzikos, K.; Pachynski, R.; Penny, R.; Piert, M.; Purysko, A.; Rais-Bahrami, S.; Savir-Baruch, B.; Somford, R.; Tewari, A.; Uchio, E.; Yoo, D.; Zukotynski, K. Diagnostic performance and safety of 18 F-RhPSMA-7.3 Positron emission tomography in men with suspected prostate cancer recurrence: Results from a phase 3, prospective, multicenter study (SPOTLIGHT). J. Urol.,  2023, 10-1097.

[133]
Kroenke, M.; Schweiger, L.; Horn, T.; Haller, B.; Schwamborn, K.; Wurzer, A.; Maurer, T.; Wester, H.J.; Eiber, M.; Rauscher, I. Validation of 18 F-rhPSMA-7 and 18 F-rhPSMA-7.3 PET imaging results with histopathology from salvage surgery in patients with biochemical recurrence of prostate cancer. J. Nucl. Med.,  2022, 63(12), 1809-1814.
 [http://dx.doi.org/10.2967/jnumed.121.263707] [PMID: 35393348]

[134]
Yusufi, N.; Wurzer, A.; Herz, M.; D’Alessandria, C.; Feuerecker, B.; Weber, W.; Wester, H.J.; Nekolla, S.; Eiber, M. Comparative preclinical biodistribution, dosimetry, and endoradiotherapy in metastatic castration-resistant prostate cancer using 19 F/177 Lu-rhPSMA-7.3 and 177 Lu-PSMA I&T. J. Nucl. Med.,  2021, 62(8), 1106-1111.
 [http://dx.doi.org/10.2967/jnumed.120.254516] [PMID: 33443072]

[135]
Feuerecker, B.; Chantadisai, M.; Allmann, A.; Tauber, R.; Allmann, J.; Steinhelfer, L.; Rauscher, I.; Wurzer, A.; Wester, H.J.; Weber, W.A.; d’Alessandria, C.; Eiber, M. Pretherapeutic comparative dosimetry of 177 Lu-rhPSMA-7.3 and 177 Lu-PSMA I&T in patients with metastatic castration-resistant prostate cancer. J. Nucl. Med.,  2022, 63(6), 833-839.
 [http://dx.doi.org/10.2967/jnumed.121.262671] [PMID: 34531260]

[136]
Rousseau, E.; Lau, J.; Kuo, H.T.; Zhang, Z.; Merkens, H.; Hundal-Jabal, N.; Colpo, N.; Lin, K.S.; Bénard, F. Monosodium glutamate reduces 68 Ga-PSMA-11 uptake in salivary glands and kidneys in a preclinical prostate cancer model. J. Nucl. Med.,  2018, 59(12), 1865-1868.
 [http://dx.doi.org/10.2967/jnumed.118.215350] [PMID: 30097503]

[137]
Rupp, N.J.; Umbricht, C.A.; Pizzuto, D.A.; Lenggenhager, D.; Töpfer, A.; Müller, J.; Muehlematter, U.J.; Ferraro, D.A.; Messerli, M.; Morand, G.B.; Huber, G.F.; Eberli, D.; Schibli, R.; Müller, C.; Burger, I.A. First clinicopathologic evidence of a Non–PSMA-related uptake mechanism for 68 Ga-PSMA-11 in salivary glands. J. Nucl. Med.,  2019, 60(9), 1270-1276.
 [http://dx.doi.org/10.2967/jnumed.118.222307] [PMID: 30737300]

[138]
Szabo, Z.; Mena, E.; Rowe, S.P.; Plyku, D.; Nidal, R.; Eisenberger, M.A.; Antonarakis, E.S.; Fan, H.; Dannals, R.F.; Chen, Y.; Mease, R.C.; Vranesic, M.; Bhatnagar, A.; Sgouros, G.; Cho, S.Y.; Pomper, M.G. Initial evaluation of [18F]DCFPyL for prostate-specific membrane antigen (PSMA)-Targeted PET imaging of prostate cancer. Mol. Imaging Biol.,  2015, 17(4), 565-574.
 [http://dx.doi.org/10.1007/s11307-015-0850-8] [PMID: 25896814]

[139]
Hillier, S.M.; Maresca, K.P.; Femia, F.J.; Marquis, J.C.; Foss, C.A.; Nguyen, N.; Zimmerman, C.N.; Barrett, J.A.; Eckelman, W.C.; Pomper, M.G.; Joyal, J.L.; Babich, J.W. Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer. Cancer Res.,  2009, 69(17), 6932-6940.
 [http://dx.doi.org/10.1158/0008-5472.CAN-09-1682] [PMID: 19706750]

[140]
Kratochwil, C.; Giesel, F.L.; Eder, M.; Afshar-Oromieh, A.; Benešová, M.; Mier, W.; Kopka, K.; Haberkorn, U. [177Lu]Lutetium-labelled PSMA ligand-induced remission in a patient with metastatic prostate cancer. Eur. J. Nucl. Med. Mol. Imaging,  2015, 42(6), 987-988.
 [http://dx.doi.org/10.1007/s00259-014-2978-1] [PMID: 25573634]

[141]
Tolvanen, T.; Kalliokoski, K.; Malaspina, S.; Kuisma, A.; Lahdenpohja, S.; Postema, E.J.; Miller, M.P.; Scheinin, M. Safety, biodistribution, and radiation dosimetry of 18 F-rhPSMA-7.3 in healthy adult volunteers. J. Nucl. Med.,  2021, 62(5), 679-684.
 [http://dx.doi.org/10.2967/jnumed.120.252114] [PMID: 33067338]

[142]
Malaspina, S.; Oikonen, V.; Kuisma, A.; Ettala, O.; Mattila, K.; Boström, P.J.; Minn, H.; Kalliokoski, K.; Postema, E.J.; Miller, M.P.; Scheinin, M. Kinetic analysis and optimisation of 18F-rhPSMA-7.3 PET imaging of prostate cancer. Eur. J. Nucl. Med. Mol. Imaging,  2021, 48(11), 3723-3731.
 [http://dx.doi.org/10.1007/s00259-021-05346-8] [PMID: 33846844]

[143]
Park, J.E.; Lenter, M.C.; Zimmermann, R.N.; Garin-Chesa, P.; Old, L.J.; Rettig, W.J. Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J. Biol. Chem.,  1999, 274(51), 36505-36512.
 [http://dx.doi.org/10.1074/jbc.274.51.36505] [PMID: 10593948]

[144]
Teichgräber, V.; Monasterio, C.; Chaitanya, K.; Boger, R.; Gordon, K.; Dieterle, T.; Jäger, D.; Bauer, S. Specific inhibition of fibroblast activation protein (FAP)-alpha prevents tumor progression in vitro. Adv. Med. Sci.,  2015, 60(2), 264-272.
 [http://dx.doi.org/10.1016/j.advms.2015.04.006] [PMID: 26057860]

[145]
Yamamura, Y.; Asai, N.; Enomoto, A.; Kato, T.; Mii, S.; Kondo, Y.; Ushida, K.; Niimi, K.; Tsunoda, N.; Nagino, M.; Ichihara, S.; Furukawa, K.; Maeda, K.; Murohara, T.; Takahashi, M. Akt-girdin signaling in cancer-associated fibroblasts contributes to tumor progression. Cancer Res.,  2015, 75(5), 813-823.
 [http://dx.doi.org/10.1158/0008-5472.CAN-14-1317] [PMID: 25732845]

[146]
Shiga, K.; Hara, M.; Nagasaki, T.; Sato, T.; Takahashi, H.; Takeyama, H. Cancer-associated fibroblasts: Their characteristics and their roles in tumor growth. Cancers.,  2015, 7(4), 2443-2458.
 [http://dx.doi.org/10.3390/cancers7040902] [PMID: 26690480]

[147]
Rettig, W.J.; Chesa, P.G.; Beresford, H.R.; Feickert, H.J.; Jennings, M.T.; Cohen, J.; Oettgen, H.F.; Old, L.J. Differential expression of cell surface antigens and glial fibrillary acidic protein in human astrocytoma subsets. Cancer Res.,  1986, 46(12 Pt 1), 6406-6412.
 [PMID: 2877731]

[148]
Scanlan, M.J.; Raj, B.K.; Calvo, B.; Garin-Chesa, P.; Sanz-Moncasi, M.P.; Healey, J.H.; Old, L.J.; Rettig, W.J. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc. Natl. Acad. Sci.,  1994, 91(12), 5657-5661.
 [http://dx.doi.org/10.1073/pnas.91.12.5657] [PMID: 7911242]

[149]
Garin-Chesa, P.; Old, L.J.; Rettig, W.J. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc. Natl. Acad. Sci.,  1990, 87(18), 7235-7239.
 [http://dx.doi.org/10.1073/pnas.87.18.7235] [PMID: 2402505]

[150]
Kelly, T.; Kechelava, S.; Rozypal, T.L.; West, K.W.; Korourian, S. Seprase, a membrane-bound protease, is overexpressed by invasive ductal carcinoma cells of human breast cancers. Mod. Pathol.,  1998, 11(9), 855-863.
 [PMID: 9758365]

[151]
Jin, X.; Iwasa, S.; Okada, K.; Mitsumata, M.; Ooi, A. Expression patterns of seprase, a membrane serine protease, in cervical carcinoma and cervical intraepithelial neoplasm. Anticancer Res.,  2003, 23(4), 3195-3198.
 [PMID: 12926053]

[152]
Mori, Y.; Kono, K.; Matsumoto, Y.; Fujii, H.; Yamane, T.; Mitsumata, M.; Chen, W.T. The expression of a type II transmembrane serine protease (Seprase) in human gastric carcinoma. Oncology.,  2004, 67(5-6), 411-419.
 [http://dx.doi.org/10.1159/000082926] [PMID: 15713998]

[153]
Jansen, K.; Heirbaut, L.; Cheng, J.D.; Joossens, J.; Ryabtsova, O.; Cos, P.; Maes, L.; Lambeir, A.M.; De Meester, I.; Augustyns, K.; Van der Veken, P. Selective inhibitors of fibroblast activation protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine scaffold. ACS Med. Chem. Lett.,  2013, 4(5), 491-496.
 [http://dx.doi.org/10.1021/ml300410d] [PMID: 24900696]

[154]
Jansen, K.; Heirbaut, L.; Verkerk, R.; Cheng, J.D.; Joossens, J.; Cos, P.; Maes, L.; Lambeir, A.M.; De Meester, I.; Augustyns, K.; Van der Veken, P. Extended structure-activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP). J. Med. Chem.,  2014, 57(7), 3053-3074.
 [http://dx.doi.org/10.1021/jm500031w] [PMID: 24617858]

[155]
Loktev, A.; Lindner, T.; Mier, W.; Debus, J.; Altmann, A.; Jäger, D.; Giesel, F.; Kratochwil, C.; Barthe, P.; Roumestand, C.; Haberkorn, U. A tumor-imaging method targeting cancer-associated fibroblasts. J. Nucl. Med.,  2018, 59(9), 1423-1429.
 [http://dx.doi.org/10.2967/jnumed.118.210435] [PMID: 29626120]

[156]
Giesel, F.L.; Kratochwil, C.; Lindner, T.; Marschalek, M.M.; Loktev, A.; Lehnert, W.; Debus, J.; Jäger, D.; Flechsig, P.; Altmann, A.; Mier, W.; Haberkorn, U. 68 Ga-FAPI PET/CT: Biodistribution and preliminary dosimetry estimate of 2 DOTA-containing FAP-targeting agents in patients with various cancers. J. Nucl. Med.,  2019, 60(3), 386-392.
 [http://dx.doi.org/10.2967/jnumed.118.215913] [PMID: 30072500]

[157]
68Ga-FAPI PET/CT in patients with various types of cancer. Patent NCT04499365, 2020.

[158]
68Ga-FAPi-46 PET/CT scan in imaging patients with sarcoma. Patent NCT04457258, 2023.

[159]
Experimental PET imaging scans before cancer surgery to study the amount of PET tracer accumulated in normal and cancer tissues. Patent NCT04147494, 2021.

[160]
Giesel, F.L.; Kratochwil, C.; Schlittenhardt, J.; Dendl, K.; Eiber, M.; Staudinger, F.; Kessler, L.; Fendler, W.P.; Lindner, T.; Koerber, S.A.; Cardinale, J.; Sennung, D.; Roehrich, M.; Debus, J.; Sathekge, M.; Haberkorn, U.; Calais, J.; Serfling, S.; Buck, A.L. Head-to-head intra-individual comparison of biodistribution and tumor uptake of 68Ga-FAPI and 18F-FDG PET/CT in cancer patients. Eur. J. Nucl. Med. Mol. Imaging,  2021, 48(13), 4377-4385.
 [http://dx.doi.org/10.1007/s00259-021-05307-1] [PMID: 34137945]

[161]
Zhao, L.; Pang, Y.; Luo, Z.; Fu, K.; Yang, T.; Zhao, L.; Sun, L.; Wu, H.; Lin, Q.; Chen, H. Role of [68Ga]Ga-DOTA-FAPI-04 PET/CT in the evaluation of peritoneal carcinomatosis and comparison with [18F]-FDG PET/CT. Eur. J. Nucl. Med. Mol. Imaging,  2021, 48(6), 1944-1955.
 [http://dx.doi.org/10.1007/s00259-020-05146-6] [PMID: 33415432]

[162]
Zhao, L.; Chen, J.; Pang, Y.; Fu, K.; Shang, Q.; Wu, H.; Sun, L.; Lin, Q.; Chen, H. Fibroblast activation protein-based theranostics in cancer research: A state-of-the-art review. Theranostics.,  2022, 12(4), 1557-1569.
 [http://dx.doi.org/10.7150/thno.69475] [PMID: 35198057]

[163]
Zhao, L.; Niu, B.; Fang, J.; Pang, Y.; Li, S.; Xie, C.; Sun, L.; Zhang, X.; Guo, Z.; Lin, Q.; Chen, H. Synthesis, preclinical evaluation, and a pilot clinical PET imaging study of 68Ga-labeled FAPI dimer. J. Nucl. Med.,  2021, 63(6), 862-868.

[164]
Xu, M.; Zhang, P.; Ding, J.; Chen, J.; Huo, L.; Liu, Z. Albumin binder–conjugated fibroblast activation protein inhibitor radiopharmaceuticals for cancer therapy. J. Nucl. Med.,  2021, 63(6), 952-958.

[165]
Wen, X.; Xu, P.; Shi, M.; Liu, J.; Zeng, X.; Zhang, Y.; Shi, C.; Li, J.; Guo, Z.; Zhang, X.; Khong, P.L.; Chen, X. Evans blue-modified radiolabeled fibroblast activation protein inhibitor as long-acting cancer therapeutics. Theranostics,  2022, 12(1), 422-433.
 [http://dx.doi.org/10.7150/thno.68182] [PMID: 34987657]

[166]
Scheltens, P.; Blennow, K.; Breteler, M.M.B.; de Strooper, B.; Frisoni, G.B.; Salloway, S.; Van der Flier, W.M. Alzheimer’s disease. Lancet,  2016, 388(10043), 505-517.
 [http://dx.doi.org/10.1016/S0140-6736(15)01124-1] [PMID: 26921134]

[167]
Giorgetti, S.; Greco, C.; Tortora, P.; Aprile, F. Targeting amyloid aggregation: An overview of strategies and mechanisms. Int. J. Mol. Sci.,  2018, 19(9), 2677.
 [http://dx.doi.org/10.3390/ijms19092677] [PMID: 30205618]

[168]
Walsh, D.; Selkoe, D. Oligomers on the brain: The emerging role of soluble protein aggregates in neurodegeneration. Protein Pept. Lett.,  2004, 11(3), 213-228.
 [http://dx.doi.org/10.2174/0929866043407174] [PMID: 15182223]

[169]
Awasthi, M.; Singh, S.; Pandey, V.P.; Dwivedi, U.N. Alzheimer’s disease: An overview of amyloid beta dependent pathogenesis and its therapeutic implications along with in silico approaches emphasizing the role of natural products. J. Neurol. Sci.,  2016, 361, 256-271.
 [http://dx.doi.org/10.1016/j.jns.2016.01.008] [PMID: 26810552]

[170]
Villemagne, V.L. Amyloid imaging: Past, present and future perspectives. Ageing Res. Rev.,  2016, 30, 95-106.
 [http://dx.doi.org/10.1016/j.arr.2016.01.005] [PMID: 26827784]

[171]
Mathis, C.A.; Lopresti, B.J.; Ikonomovic, M.D.; Klunk, W.E. Small-molecule PET tracers for imaging proteinopathies. Semin. Nucl. Med.,  2017, 47(5), 553-575.
 [http://dx.doi.org/10.1053/j.semnuclmed.2017.06.003] [PMID: 28826526]

[172]
Chiti, F.; Dobson, C.M. Protein misfolding, amyloid formation, and human disease: A summary of progress over the last decade. Annu. Rev. Biochem.,  2017, 86(1), 27-68.
 [http://dx.doi.org/10.1146/annurev-biochem-061516-045115] [PMID: 28498720]

[173]
Lacerda, S.; Morfin, J.F.; Geraldes, C.F.G.C.; Tóth, É. Metal complexes for multimodal imaging of misfolded protein-related diseases. Dalton Trans.,  2017, 46(42), 14461-14474.
 [http://dx.doi.org/10.1039/C7DT02371E] [PMID: 28952628]

[174]
Prince, M.J.; Wimo, A.; Guerchet, M.M.; Ali, G.C.; Wu, Y.T.; Prina, M. 2015. The Global Impact of Dementia. An Analysis of Prevalence, Incidence, Cost and Trends. Available from:  https://www.alzint.org/u/WorldAlzheimerReport2015.pdf

[175]
Hardy, J. Testing times for the “amyloid cascade hypothesis”. Neurobiol. Aging,  2002, 23(6), 1073-1074.
 [http://dx.doi.org/10.1016/S0197-4580(02)00042-8] [PMID: 12470803]

[176]
Karran, E.; Mercken, M.; Strooper, B.D. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov.,  2011, 10(9), 698-712.
 [http://dx.doi.org/10.1038/nrd3505] [PMID: 21852788]

[177]
Zhang, Y.; Thompson, R.; Zhang, H.; Xu, H. APP processing in Alzheimer’s disease. Mol. Brain,  2011, 4(1), 3.
 [http://dx.doi.org/10.1186/1756-6606-4-3] [PMID: 21214928]

[178]
Sipe, J.D.; Benson, M.D.; Buxbaum, J.N.; Ikeda, S.; Merlini, G.; Saraiva, M.J.M.; Westermark, P. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid,  2016, 23(4), 209-213.
 [http://dx.doi.org/10.1080/13506129.2016.1257986] [PMID: 27884064]

[179]
Kaur, A.; New, E.J.; Sunde, M. Strategies for the molecular imaging of amyloid and the value of a multimodal approach. ACS Sens.,  2020, 5(8), 2268-2282.
 [http://dx.doi.org/10.1021/acssensors.0c01101] [PMID: 32627533]

[180]
Pike, V.W. Considerations in the development of reversibly binding PET radioligands for brain imaging. Curr. Med. Chem.,  2016, 23(18), 1818-1869.
 [http://dx.doi.org/10.2174/0929867323666160418114826] [PMID: 27087244]

[181]
Furumoto, S.; Okamura, N.; Iwata, R.; Yanai, K.; Arai, H.; Kudo, Y. Recent advances in the development of amyloid imaging agents. Curr. Top. Med. Chem.,  2007, 7(18), 1773-1789.
 [http://dx.doi.org/10.2174/156802607782507402] [PMID: 17979786]

[182]
Zhang, L.; Villalobos, A. Strategies to facilitate the discovery of novel CNS PET ligands. EJNMMI Radiopharm. Chem.,  2017, 1(1), 13.
 [http://dx.doi.org/10.1186/s41181-016-0016-2] [PMID: 29564389]

[183]
Uzuegbunam, B.C.; Librizzi, D.; Hooshyar, Y.B. PET radiopharmaceuticals for Alzheimer’s disease and Parkinson’s disease diagnosis, the current and future landscape. Molecules,  2020, 25(4), 977.
 [http://dx.doi.org/10.3390/molecules25040977] [PMID: 32098280]

[184]
Hayne, D.J.; Lim, S.; Donnelly, P.S. Metal complexes designed to bind to amyloid-β for the diagnosis and treatment of Alzheimer’s disease. Chem. Soc. Rev.,  2014, 43(19), 6701-6715.
 [http://dx.doi.org/10.1039/C4CS00026A] [PMID: 24671229]

[185]
Papagiannopoulou, D.; Hadjipavlou-Litina, D. Computational modeling of diagnostic imaging agents for Alzheimer’s disease: Molecular imaging agents for the in vivo detection of amyloid plaques in Alzheimer’s disease. In: Neuromethods; Humana Press Inc., 2018; Vol. 132, pp. 463-479.

[186]
Zeng, F.; Goodman, M.M. Fluorine-18 radiolabeled heterocycles as PET tracers for imaging β-amyloid plaques in Alzheimer’s disease. Curr. Top. Med. Chem.,  2013, 13(8), 909-919.
 [http://dx.doi.org/10.2174/1568026611313080004] [PMID: 23590167]

[187]
Xu, M.; Ren, W.; Tang, X.; Hu, Y.; Zhang, H. Advances in development of fluorescent probes for detecting amyloid-β aggregates. Acta Pharmacol. Sin.,  2016, 37(6), 719-730.
 [http://dx.doi.org/10.1038/aps.2015.155] [PMID: 26997567]

[188]
Eckroat, T.J.; Mayhoub, A.S.; Garneau-Tsodikova, S. Amyloid-β probes: Review of structure–activity and brain-kinetics relationships. Beilstein J. Org. Chem.,  2013, 9, 1012-1044.
 [http://dx.doi.org/10.3762/bjoc.9.116] [PMID: 23766818]

[189]
Zhu, L.; Ploessl, K.; Kung, H.F. PET/SPECT imaging agents for neurodegenerative diseases. Chem. Soc. Rev.,  2014, 43(19), 6683-6691.
 [http://dx.doi.org/10.1039/C3CS60430F] [PMID: 24676152]

[190]
Ono, M.; Saji, H. Recent advances in molecular imaging probes for β-amyloid plaques. MedChemComm,  2015, 6(3), 391-402.
 [http://dx.doi.org/10.1039/C4MD00365A]

[191]
Mathis, C.A.; Mason, N.S.; Lopresti, B.J.; Klunk, W.E. Development of positron emission tomography β-amyloid plaque imaging agents. Semin. Nucl. Med.,  2012, 42(6), 423-432.
 [http://dx.doi.org/10.1053/j.semnuclmed.2012.07.001] [PMID: 23026364]

[192]
Li, Z.; Cui, M.; Dai, J.; Wang, X.; Yu, P.; Yang, Y.; Jia, J.; Fu, H.; Ono, M.; Jia, H.; Saji, H.; Liu, B. Novel cyclopentadienyl tricarbonyl complexes of (99m)Tc mimicking chalcone as potential single-photon emission computed tomography imaging probes for β-amyloid plaques in brain. J. Med. Chem.,  2013, 56(2), 471-482.
 [http://dx.doi.org/10.1021/jm3014184] [PMID: 23240831]

[193]
Barrio, J.; Huang, S.; Cole, G.; Satyamurthy, N.; Petric, A.; Phelps, M.; Small, G. PET imaging of tangles and plaques in alzheimer disease with a highly hydrophobic probe. J. Labelled Comp. Radiopharm.,  1999, 42, S194-S195.

[194]
Agdeppa, E.; Kepe, V.; Liu, J.; Small, G.W.; Huang, S.C.; Petrič, A.; Satyamurthy, N.; Barrio, J.R. 2-dialkylamino-6-acylmalononitrile substituted naphthalenes (DDNP analogs): novel diagnostic and therapeutic tools in Alzheimer’s disease. Mol. Imaging Biol.,  2003, 5(6), 404-417.
 [http://dx.doi.org/10.1016/j.mibio.2003.09.010] [PMID: 14667495]

[195]
Agdeppa, E.D.; Kepe, V.; Liu, J.; Flores-Torres, S.; Satyamurthy, N.; Petric, A.; Cole, G.M.; Small, G.W.; Huang, S.C.; Barrio, J.R. Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer’s disease. J. Neurosci.,  2001, 21(24), RC189-RC189.
 [http://dx.doi.org/10.1523/JNEUROSCI.21-24-j0004.2001] [PMID: 11734604]

[196]
Agdeppa, E.D.; Kepe, V.; Petri, A.; Satyamurthy, N.; Liu, J.; Huang, S.C.; Small, G.W.; Cole, G.M.; Barrio, J.R. In vitro detection of (S)-naproxen and ibuprofen binding to plaques in the Alzheimer’s brain using the positron emission tomography molecular imaging probe 2-(1-[6-[(2-[(18)F]fluoroethyl)(methyl)amino]-2-naphthyl]ethylidene)malononitrile. Neuroscience,  2003, 117(3), 723-730.
 [http://dx.doi.org/10.1016/S0306-4522(02)00907-7] [PMID: 12617976]

[197]
Klunk, W.E.; Wang, Y.; Huang, G.; Debnath, M.L.; Holt, D.P.; Mathis, C.A. Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain. Life Sci.,  2001, 69(13), 1471-1484.
 [http://dx.doi.org/10.1016/S0024-3205(01)01232-2] [PMID: 11554609]

[198]
Mathis, C.A.; Wang, Y.; Holt, D.P.; Huang, G.F.; Debnath, M.L.; Klunk, W.E. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J. Med. Chem.,  2003, 46(13), 2740-2754.
 [http://dx.doi.org/10.1021/jm030026b] [PMID: 12801237]

[199]
Klunk, W.E.; Engler, H.; Nordberg, A.; Wang, Y.; Blomqvist, G.; Holt, D.P.; Bergström, M.; Savitcheva, I.; Huang, G.F.; Estrada, S.; Ausén, B.; Debnath, M.L.; Barletta, J.; Price, J.C.; Sandell, J.; Lopresti, B.J.; Wall, A.; Koivisto, P.; Antoni, G.; Mathis, C.A.; Långström, B. Imaging brain amyloid in Alzheimer’s disease with pittsburgh compound-B. Ann. Neurol.,  2004, 55(3), 306-319.
 [http://dx.doi.org/10.1002/ana.20009] [PMID: 14991808]

[200]
Pilebro, B.; Arvidsson, S.; Lindqvist, P.; Sundström, T.; Westermark, P.; Antoni, G.; Suhr, O.; Sörensen, J. Positron emission tomography (PET) utilizing Pittsburgh compound B (PIB) for detection of amyloid heart deposits in hereditary transthyretin amyloidosis (ATTR). J. Nucl. Cardiol.,  2018, 25(1), 240-248.
 [http://dx.doi.org/10.1007/s12350-016-0638-5] [PMID: 27645889]

[201]
Yousefi, B.H.; von Reutern, B.; Scherübl, D.; Manook, A.; Schwaiger, M.; Grimmer, T.; Henriksen, G.; Förster, S.; Drzezga, A.; Wester, H.J. FIBT versus florbetaben and PiB: A preclinical comparison study with amyloid-PET in transgenic mice. EJNMMI Res.,  2015, 5(1), 20.
 [http://dx.doi.org/10.1186/s13550-015-0090-6] [PMID: 25918674]

[202]
de Lartigue, J. Flutemetamol (18F): A β-amyloid positron emission tomography tracer for Alzheimer’s and dementia diagnosis. Drugs Today,  2014, 50(3), 219-229.
 [http://dx.doi.org/10.1358/dot.2014.50.3.2116672] [PMID: 24696867]

[203]
Davis, P. Application Number: 203137Orig1s000. Vizamyl (Flutemetamol F18 Injection). Med. Rev.,  2013, 3-69.

[204]
Kimura, Y.; Kato, T.; Ito, K.; Ichise, M. SPECT and PET of the brain. In: Clinical Nuclear Medicine; Ahmadzadehfar, H.; Biersack, H.; Freeman, L.; Zuckier, L., Eds.; Springer: Cham, 2020. 
 [http://dx.doi.org/10.1007/978-3-030-39457-8_4]

[205]
Kung, H.F.; Choi, S.R.; Qu, W.; Zhang, W.; Skovronsky, D. 18F stilbenes and styrylpyridines for PET imaging of A β plaques in Alzheimer’s disease: A miniperspective. J. Med. Chem.,  2010, 53(3), 933-941.
 [http://dx.doi.org/10.1021/jm901039z] [PMID: 19845387]

[206]
Ono, M.; Wilson, A.; Nobrega, J.; Westaway, D.; Verhoeff, P.; Zhuang, Z.P.; Kung, M.P.; Kung, H.F. 11C-labeled stilbene derivatives as Aβ-aggregate-specific PET imaging agents for Alzheimer’s disease. Nucl. Med. Biol.,  2003, 30(6), 565-571.
 [http://dx.doi.org/10.1016/S0969-8051(03)00049-0] [PMID: 12900282]

[207]
Verhoeff, N.P.; Wilson, A.A.; Takeshita, S.; Trop, L.; Hussey, D.; Singh, K.; Kung, H.F.; Kung, M.P.; Houle, S. In-vivo imaging of Alzheimer disease beta-amyloid with [11C]SB-13 PET. Am. J. Geriatr. Psychiatry,  2004, 12(6), 584-595.
 [PMID: 15545326]

[208]
Zhang, W.; Oya, S.; Kung, M.P.; Hou, C.; Maier, D.L.; Kung, H.F. F-18 stilbenes as PET imaging agents for detecting β-amyloid plaques in the brain. J. Med. Chem.,  2005, 48(19), 5980-5988.
 [http://dx.doi.org/10.1021/jm050166g] [PMID: 16162001]

[209]
Ribeiro Morais, G.; Paulo, A.; Santos, I. A synthetic overview of radiolabeled compounds for β-amyloid targeting. Eur. J. Org. Chem.,  2012, 2012(7), 1279-1293.
 [http://dx.doi.org/10.1002/ejoc.201101449]

[210]
Zhang, W.; Kung, M.P.; Oya, S.; Hou, C.; Kung, H.F. 18F-labeled styrylpyridines as PET agents for amyloid plaque imaging. Nucl. Med. Biol.,  2007, 34(1), 89-97.
 [http://dx.doi.org/10.1016/j.nucmedbio.2006.10.003] [PMID: 17210465]

[211]
Choi, S.R.; Schneider, J.A.; Bennett, D.A.; Beach, T.G.; Bedell, B.J.; Zehntner, S.P.; Krautkramer, M.J.; Kung, H.F.; Skovronsky, D.M.; Hefti, F.; Clark, C.M. Correlation of amyloid PET ligand florbetapir F 18 binding with Aβ aggregation and neuritic plaque deposition in postmortem brain tissue. Alzheimer Dis. Assoc. Disord.,  2012, 26(1), 8-16.
 [http://dx.doi.org/10.1097/WAD.0b013e31821300bc] [PMID: 22354138]

[212]
Zhuang, Z.P.; Kung, M.P.; Wilson, A.; Lee, C.W.; Plössl, K.; Hou, C.; Holtzman, D.M.; Kung, H.F. Structure-activity relationship of imidazo[1,2-a]pyridines as ligands for detecting β-amyloid plaques in the brain. J. Med. Chem.,  2003, 46(2), 237-243.
 [http://dx.doi.org/10.1021/jm020351j] [PMID: 12519062]

[213]
Newberg, A.B.; Wintering, N.A.; Plössl, K.; Hochold, J.; Stabin, M.G.; Watson, M.; Skovronsky, D.; Clark, C.M.; Kung, M-P.; Kung, H.F. Safety, biodistribution, and dosimetry of 123I-IMPY: A novel amyloid plaque-imaging agent for the diagnosis of Alzheimer’s disease. J. Nucl. Med.,  2006, 47(5), 748-754.
 [PMID: 16644743]

[214]
Chang, K.W.; Chen, C.C.; Lee, S.Y.; Shen, L.H.; Wang, H.E. The synthesis and characterization of [124I]IMPY, a thioflavin-S derivative, in transgenic mouse models of Alzheimer’s disease. Appl. Radiat. Isot.,  2009, 67(7-8), 1397-1400.
 [http://dx.doi.org/10.1016/j.apradiso.2009.02.039] [PMID: 19307132]

[215]
Kung, M.P.; Lin, K-J.; Hsiao, I-T.; Weng, C-C.; Yen, T.C.; Wey, S.P. Amyloid plaque imaging from IMPY/SPECT to AV-45/PET. Biomed. J.,  2012, 35(3), 211-218.
 [http://dx.doi.org/10.4103/2319-4170.106151] [PMID: 22735052]

[216]
Chen, C.J.; Bando, K.; Ashino, H.; Taguchi, K.; Shiraishi, H.; Shima, K.; Fujimoto, O.; Kitamura, C.; Matsushima, S.; Uchida, K.; Nakahara, Y.; Kasahara, H.; Minamizawa, T.; Jiang, C.; Zhang, M.R.; Ono, M.; Tokunaga, M.; Suhara, T.; Higuchi, M.; Yamada, K.; Ji, B. In vivo SPECT imaging of amyloid-β deposition with radioiodinated imidazo[1,2-a]pyridine derivative DRM106 in a mouse model of Alzheimer’s disease. J. Nucl. Med.,  2015, 56(1), 120-126.
 [http://dx.doi.org/10.2967/jnumed.114.146944] [PMID: 25476539]

[217]
Okumura, Y.; Maya, Y.; Onishi, T.; Shoyama, Y.; Izawa, A.; Nakamura, D.; Tanifuji, S.; Tanaka, A.; Arano, Y.; Matsumoto, H. Design, synthesis, and preliminary evaluation of SPECT probes for imaging β-amyloid in alzheimer’s disease affected brain. ACS Chem. Neurosci.,  2018, 9(6), 1503-1514.
 [http://dx.doi.org/10.1021/acschemneuro.8b00064] [PMID: 29580057]

[218]
Sedgwick, A.C.; Brewster, J.T.; Harvey, P.; Iovan, D.A.; Smith, G.; He, X.P.; Tian, H.; Sessler, J.L.; James, T.D. Metal-based imaging agents: Progress towards interrogating neurodegenerative disease. Chem. Soc. Rev.,  2020, 49(10), 2886-2915.
 [http://dx.doi.org/10.1039/C8CS00986D] [PMID: 32226991]

[219]
Serdons, K.; Verduyckt, T.; Cleynhens, J.; Terwinghe, C.; Mortelmans, L.; Bormans, G.; Verbruggen, A. Synthesis and evaluation of a 99mTc-BAT-phenylbenzothiazole conjugate as a potential in vivo tracer for visualization of amyloid β. Bioorg. Med. Chem. Lett.,  2007, 17(22), 6086-6090.
 [http://dx.doi.org/10.1016/j.bmcl.2007.09.055] [PMID: 17904367]

[220]
Molavipordanjani, S.; Emami, S.; Hosseinimehr, S.J. 99mTc-labeled small molecules for diagnosis of Alzheimer’s disease: Past, recent and future perspectives. Curr. Med. Chem.,  2019, 26(12), 2166-2189.
 [http://dx.doi.org/10.2174/0929867325666180410104023] [PMID: 29637851]

[221]
Zhang, X.; Yu, P.; Yang, Y.; Hou, Y.; Peng, C.; Liang, Z.; Lu, J.; Chen, B.; Dai, J.; Liu, B.; Cui, M. 99m Tc-Labeled 2-Arylbenzothiazoles: Aβ imaging probes with favorable brain pharmacokinetics for single-photon emission computed tomography. Bioconjug. Chem.,  2016, 27(10), 2493-2504.
 [http://dx.doi.org/10.1021/acs.bioconjchem.6b00444] [PMID: 27668687]

[222]
Krasnovskaya, O.; Spector, D.; Zlobin, A.; Pavlov, K.; Gorelkin, P.; Erofeev, A.; Beloglazkina, E.; Majouga, A. Metals in imaging of Alzheimer’s disease. Int. J. Mol. Sci.,  2020, 21(23), 9190.
 [http://dx.doi.org/10.3390/ijms21239190] [PMID: 33276505]

[223]
Chen, K.; Cui, M. Recent progress in the development of metal complexes as β-amyloid imaging probes in the brain. MedChemComm.,  2017, 8(7), 1393-1407.
 [http://dx.doi.org/10.1039/C7MD00064B] [PMID: 30108850]

[224]
Jokar, S.; Behnammanesh, H.; Erfani, M.; Sharifzadeh, M.; Gholami, M.; Sabzevari, O.; Amini, M.; Geramifar, P.; Hajiramezanali, M.; Beiki, D. Synthesis, biological evaluation and preclinical study of a novel 99mTc-peptide: A targeting probe of amyloid-β plaques as a possible diagnostic agent for Alzheimer’s disease. Bioorg. Chem.,  2020, 99, 103857.
 [http://dx.doi.org/10.1016/j.bioorg.2020.103857] [PMID: 32330736]

[225]
Xu, M.; Guo, J.; Gu, J.; Zhang, L.; Liu, Z.; Ding, L.; Fu, H.; Ma, Y.; Liang, S.; Wang, H. Preclinical and clinical study on [18F]DRKXH1: a novel β-amyloid PET tracer for Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging,  2022, 49(2), 652-663.
 [http://dx.doi.org/10.1007/s00259-021-05421-0] [PMID: 34292345]

[226]
Rivera-Marrero, S.; Fernández-Maza, L.; León-Chaviano, S.; Sablón-Carrazana, M.; Bencomo-Martínez, A.; Perera-Pintado, A.; Prats-Capote, A.; Zoppolo, F.; Kreimerman, I.; Pardo, T.; Reyes, L.; Balcerzyk, M.; Dubed-Bandomo, G.; Mercerón-Martínez, D.; Espinosa-Rodríguez, L.A.; Engler, H.; Savio, E.; Rodríguez-Tanty, C. [ 18 F]Amylovis as a potential PET probe for β-amyloid plaque: Synthesis, in silico, in vitro and in vivo evaluations. Curr. Radiopharm.,  2019, 12(1), 58-71.
 [http://dx.doi.org/10.2174/1874471012666190102165053] [PMID: 30605068]

[227]
Heurling, K.; Leuzy, A.; Zimmer, E.R.; Lubberink, M.; Nordberg, A. Imaging β-amyloid using [18F]flutemetamol positron emission tomography: From dosimetry to clinical diagnosis. Eur. J. Nucl. Med. Mol. Imaging,  2016, 43(2), 362-373.
 [http://dx.doi.org/10.1007/s00259-015-3208-1] [PMID: 26440450]

[228]
Zha, Z.; Ploessl, K.; Choi, S.R.; Alexoff, D.; Kung, H.F. Preclinical evaluation of [18F]D3FSP, deuterated AV-45, for imaging of β-amyloid in the brain. Nucl. Med. Biol.,  2021, 92, 97-106.
 [http://dx.doi.org/10.1016/j.nucmedbio.2020.03.003] [PMID: 32245565]

[229]
Xiao, H.; Choi, S.R.; Zhao, R.; Ploessl, K.; Alexoff, D.; Zhu, L.; Zha, Z.; Kung, H.F. A new highly deuterated [ 18 F]AV-45, [ 18 F]D15FSP, for imaging β-amyloid plaques in the brain. ACS Med. Chem. Lett.,  2021, 12(7), 1086-1092.
 [http://dx.doi.org/10.1021/acsmedchemlett.1c00062] [PMID: 34267878]

[230]
Abrahamson, E.E.; Stehouwer, J.S.; Vazquez, A.L.; Huang, G.F.; Mason, N.S.; Lopresti, B.J.; Klunk, W.E.; Mathis, C.A.; Ikonomovic, M.D. Development of a PET radioligand selective for cerebral amyloid angiopathy. Nucl. Med. Biol.,  2021, 92, 85-96.
 [http://dx.doi.org/10.1016/j.nucmedbio.2020.05.001] [PMID: 32471773]

[231]
Jia, J.; Zhang, L.; Song, J.; Dai, J.; Cui, M. Discovery of diphenoxy derivatives with flexible linkers as ligands for β-amyloid plaques. Mol. Pharm.,  2020, 17(11), 4089-4100.
 [http://dx.doi.org/10.1021/acs.molpharmaceut.0c00537] [PMID: 32845647]

[232]
Rivera-Marrero, S.; Bencomo-Martínez, A.; Orta Salazar, E.; Sablón-Carrazana, M.; García-Pupo, L.; Zoppolo, F.; Arredondo, F.; Dapueto, R.; Daniela Santi, M.; Kreimerman, I.; Pardo, T.; Reyes, L.; Galán, L.; León-Chaviano, S.; Espinosa-Rodríguez, L.A.; Menéndez-Soto del Valle, R.; Savio, E.; Díaz Cintra, S.; Rodríguez-Tanty, C. A new naphthalene derivative with anti-amyloidogenic activity as potential therapeutic agent for Alzheimer’s disease. Bioorg. Med. Chem.,  2020, 28(20), 115700.
 [http://dx.doi.org/10.1016/j.bmc.2020.115700] [PMID: 33069076]

[233]
Snellman, A.; Rokka, J.; Lopez-Picon, F.R.; Eskola, O.; Wilson, I.; Farrar, G.; Scheinin, M.; Solin, O.; Rinne, J.O.; Haaparanta-Solin, M. Pharmacokinetics of [18F]flutemetamol in wild-type rodents and its binding to beta amyloid deposits in a mouse model of Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging,  2012, 39(11), 1784-1795.
 [http://dx.doi.org/10.1007/s00259-012-2178-9] [PMID: 22801729]

[234]
Choi, S.R.; Golding, G.; Zhuang, Z.; Zhang, W.; Lim, N.; Hefti, F.; Benedum, T.E.; Kilbourn, M.R.; Skovronsky, D.; Kung, H.F. Preclinical properties of 18F-AV-45: A PET agent for Abeta plaques in the brain. J. Nucl. Med.,  2009, 50(11), 1887-1894.
 [http://dx.doi.org/10.2967/jnumed.109.065284] [PMID: 19837759]

[235]
Sundaram, G.S.M.; Dhavale, D.; Prior, J.L.; Sivapackiam, J.; Laforest, R.; Kotzbauer, P.; Sharma, V. Synthesis, characterization, and preclinical validation of a PET radiopharmaceutical for interrogating Aβ (β-amyloid) plaques in Alzheimer’s disease. EJNMMI Res.,  2015, 5(1), 33.
 [http://dx.doi.org/10.1186/s13550-015-0112-4] [PMID: 26061601]

[236]
Zhang, W.; Oya, S.; Kung, M.P.; Hou, C.; Maier, D.L.; Kung, H.F. F-18 Polyethyleneglycol stilbenes as PET imaging agents targeting Aβ aggregates in the brain. Nucl. Med. Biol.,  2005, 32(8), 799-809.
 [http://dx.doi.org/10.1016/j.nucmedbio.2005.06.001] [PMID: 16253804]

[237]
Brown, P.C. Application number:204677Orig1s000. Florbetaben. Pharmacol. Rev.,  2012, 1-246.

[238]
Dubois, B.; Hampel, H.; Feldman, H.H.; Scheltens, P.; Aisen, P.; Andrieu, S.; Bakardjian, H.; Benali, H.; Bertram, L.; Blennow, K.; Broich, K.; Cavedo, E.; Crutch, S.; Dartigues, J.F.; Duyckaerts, C.; Epelbaum, S.; Frisoni, G.B.; Gauthier, S.; Genthon, R.; Gouw, A.A.; Habert, M.O.; Holtzman, D.M.; Kivipelto, M.; Lista, S.; Molinuevo, J.L.; O’Bryant, S.E.; Rabinovici, G.D.; Rowe, C.; Salloway, S.; Schneider, L.S.; Sperling, R.; Teichmann, M.; Carrillo, M.C.; Cummings, J.; Jack, C.R., Jr Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimers Dement.,  2016, 12(3), 292-323.
 [http://dx.doi.org/10.1016/j.jalz.2016.02.002] [PMID: 27012484]

[239]
Gauthier, S.; Rosa-Neto, P.; Morais, J.A.; Webster, C. World Alzheimer Report 2021: Journey through the Diagnosis of Dementia.  2021.

[240]
Robertson, J.S.; Rowe, C.C.; Villemagne, V.L. Tau imaging with PET: An overview of challenges, current progress, and future applications. Q. J. Nucl. Med. Mol. Imaging,  2017, 61(4), 405-413.
 [http://dx.doi.org/10.23736/S1824-4785.17.03012-6] [PMID: 28750496]

[241]
Wang, Y.T.; Edison, P. Tau imaging in neurodegenerative diseases using positron emission tomography. Curr. Neurol. Neurosci. Rep.,  2019, 19(7), 45.
 [http://dx.doi.org/10.1007/s11910-019-0962-7] [PMID: 31172290]

[242]
Leuzy, A.; Chiotis, K.; Lemoine, L.; Gillberg, P.G.; Almkvist, O.; Rodriguez-Vieitez, E.; Nordberg, A. Tau PET imaging in neurodegenerative tauopathies—still a challenge. Mol. Psychiatry,  2019, 24, 1112-1134.

[243]
Villemagne, V.L.; Doré, V.; Burnham, S.C.; Masters, C.L.; Rowe, C.C. Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions. Nat. Rev. Neurol.,  2018, 14(4), 225-236.
 [http://dx.doi.org/10.1038/nrneurol.2018.9] [PMID: 29449700]

[244]
Yeung, A.W.K.; Goto, T.K.; Leung, W.K. The changing landscape of neuroscience research, 2006–2015: A bibliometric study. Front. Neurosci.,  2017, 11, 120.
 [http://dx.doi.org/10.3389/fnins.2017.00120] [PMID: 28377687]

[245]
Villemagne, V.L.; Furumoto, S.; Fodero-Tavoletti, M.; Harada, R.; Mulligan, R.S.; Kudo, Y.; Masters, C.L.; Yanai, K.; Rowe, C.C.; Okamura, N. The challenges of tau imaging. Future Neurol.,  2012, 7(4), 409-421.
 [http://dx.doi.org/10.2217/fnl.12.34]

[246]
Dani, M.; Edison, P.; Brooks, D.J. Imaging biomarkers in tauopathies. Parkinsonism Relat. Disord.,  2016, 22(S1), S26-S28.
 [http://dx.doi.org/10.1016/j.parkreldis.2015.08.011] [PMID: 26299160]

[247]
Declercq, L.; Celen, S.; Lecina, J.; Ahamed, M.; Tousseyn, T.; Moechars, D.; Alcazar, J.; Ariza, M.; Fierens, K.; Bottelbergs, A.; Mariën, J.; Vandenberghe, R.; Andres, I.J.; Van Laere, K.; Verbruggen, A.; Bormans, G. Comparison of new tau PET-tracer candidates with [ 18 F]T808 and [ 18 F]T807. Mol. Imaging,  2016, 15
 [http://dx.doi.org/10.1177/1536012115624920] [PMID: 27030397]

[248]
Shin, J.; Kepe, V.; Barrio, J.R.; Small, G.W. The merits of FDDNP-PET imaging in Alzheimer’s disease. J. Alzheimers Dis.,  2011, 26(S3), 135-145.
 [http://dx.doi.org/10.3233/JAD-2011-0008] [PMID: 21971458]

[249]
Ossenkoppele, R.; Tolboom, N.; Foster-Dingley, J.C.; Adriaanse, S.F.; Boellaard, R.; Yaqub, M.; Windhorst, A.D.; Barkhof, F.; Lammertsma, A.A.; Scheltens, P.; van der Flier, W.M.; van Berckel, B.N.M. Longitudinal imaging of Alzheimer pathology using [11C]PIB, [18F]FDDNP and [18F]FDG PET. Eur. J. Nucl. Med. Mol. Imaging,  2012, 39(6), 990-1000.
 [http://dx.doi.org/10.1007/s00259-012-2102-3] [PMID: 22441582]

[250]
Wood, H. [11C]PBB3—a new PET ligand that identifies tau pathology in the brains of patients with AD. Nat. Rev. Neurol.,  2013, 9(11), 599-599.
 [http://dx.doi.org/10.1038/nrneurol.2013.216] [PMID: 24145369]

[251]
Kimura, Y.; Ichise, M.; Ito, H.; Shimada, H.; Ikoma, Y.; Seki, C.; Takano, H.; Kitamura, S.; Shinotoh, H.; Kawamura, K.; Zhang, M.R.; Sahara, N.; Suhara, T.; Higuchi, M. PET quantification of tau pathology in human brain with 11 C-PBB3. J. Nucl. Med.,  2015, 56(9), 1359-1365.
 [http://dx.doi.org/10.2967/jnumed.115.160127] [PMID: 26182966]

[252]
Endo, H.; Shimada, H.; Sahara, N.; Ono, M.; Koga, S.; Kitamura, S.; Niwa, F.; Hirano, S.; Kimura, Y.; Ichise, M.; Shinotoh, H.; Zhang, M.R.; Kuwabara, S.; Dickson, D.W.; Toda, T.; Suhara, T.; Higuchi, M. In vivo binding of a tau imaging probe, [ 11 C]PBB3, in patients with progressive supranuclear palsy. Mov. Disord.,  2019, 34(5), 744-754.
 [http://dx.doi.org/10.1002/mds.27643] [PMID: 30892739]

[253]
Okamura, N.; Furumoto, S.; Harada, R.; Tago, T.; Yoshikawa, T.; Fodero-Tavoletti, M.; Mulligan, R.S.; Villemagne, V.L.; Akatsu, H.; Yamamoto, T.; Arai, H.; Iwata, R.; Yanai, K.; Kudo, Y. Novel 18F-labeled arylquinoline derivatives for noninvasive imaging of tau pathology in Alzheimer disease. J. Nucl. Med.,  2013, 54(8), 1420-1427.
 [http://dx.doi.org/10.2967/jnumed.112.117341] [PMID: 23857514]

[254]
Okamura, N.; Suemoto, T.; Furumoto, S.; Suzuki, M.; Shimadzu, H.; Akatsu, H.; Yamamoto, T.; Fujiwara, H.; Nemoto, M.; Maruyama, M.; Arai, H.; Yanai, K.; Sawada, T.; Kudo, Y. Quinoline and benzimidazole derivatives: Candidate probes for in vivo imaging of tau pathology in Alzheimer’s disease. J. Neurosci.,  2005, 25(47), 10857-10862.
 [http://dx.doi.org/10.1523/JNEUROSCI.1738-05.2005] [PMID: 16306398]

[255]
Fodero-Tavoletti, M.T.; Okamura, N.; Furumoto, S.; Mulligan, R.S.; Connor, A.R.; McLean, C.A.; Cao, D.; Rigopoulos, A.; Cartwright, G.A.; O’Keefe, G.; Gong, S.; Adlard, P.A.; Barnham, K.J.; Rowe, C.C.; Masters, C.L.; Kudo, Y.; Cappai, R.; Yanai, K.; Villemagne, V.L. 18F-THK523: A novel in vivo tau imaging ligand for Alzheimer’s disease. Brain,  2011, 134(4), 1089-1100.
 [http://dx.doi.org/10.1093/brain/awr038] [PMID: 21436112]

[256]
Okamura, N.; Furumoto, S.; Fodero-Tavoletti, M.T.; Mulligan, R.S.; Harada, R.; Yates, P.; Pejoska, S.; Kudo, Y.; Masters, C.L.; Yanai, K.; Rowe, C.C.; Villemagne, V.L. Non-invasive assessment of Alzheimer’s disease neurofibrillary pathology using 18F-THK5105 PET. Brain,  2014, 137(6), 1762-1771.
 [http://dx.doi.org/10.1093/brain/awu064] [PMID: 24681664]

[257]
Harada, R.; Okamura, N.; Furumoto, S.; Furukawa, K.; Ishiki, A.; Tomita, N.; Hiraoka, K.; Watanuki, S.; Shidahara, M.; Miyake, M.; Ishikawa, Y.; Matsuda, R.; Inami, A.; Yoshikawa, T.; Tago, T.; Funaki, Y.; Iwata, R.; Tashiro, M.; Yanai, K.; Arai, H.; Kudo, Y. [18F]THK-5117 PET for assessing neurofibrillary pathology in Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging,  2015, 42(7), 1052-1061.
 [http://dx.doi.org/10.1007/s00259-015-3035-4] [PMID: 25792456]

[258]
Harada, R.; Okamura, N.; Furumoto, S.; Furukawa, K.; Ishiki, A.; Tomita, N.; Tago, T.; Hiraoka, K.; Watanuki, S.; Shidahara, M.; Miyake, M.; Ishikawa, Y.; Matsuda, R.; Inami, A.; Yoshikawa, T.; Funaki, Y.; Iwata, R.; Tashiro, M.; Yanai, K.; Arai, H.; Kudo, Y. 18 F-THK5351: A novel PET radiotracer for imaging neurofibrillary pathology in alzheimer disease. J. Nucl. Med.,  2016, 57(2), 208-214.
 [http://dx.doi.org/10.2967/jnumed.115.164848] [PMID: 26541774]

[259]
Chien, D.T.; Bahri, S.; Szardenings, A.K.; Walsh, J.C.; Mu, F.; Su, M.Y.; Shankle, W.R.; Elizarov, A.; Kolb, H.C. Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807. J. Alzheimers Dis.,  2013, 34(2), 457-468.
 [http://dx.doi.org/10.3233/JAD-122059] [PMID: 23234879]

[260]
Xia, C.F.; Arteaga, J.; Chen, G.; Gangadharmath, U.; Gomez, L.F.; Kasi, D.; Lam, C.; Liang, Q.; Liu, C.; Mocharla, V.P.; Mu, F.; Sinha, A.; Su, H.; Szardenings, A.K.; Walsh, J.C.; Wang, E.; Yu, C.; Zhang, W.; Zhao, T.; Kolb, H.C. [ 18 F]T807, a novel tau positron emission tomography imaging agent for Alzheimer’s disease. Alzheimers Dement.,  2013, 9(6), 666-676.
 [http://dx.doi.org/10.1016/j.jalz.2012.11.008] [PMID: 23411393]

[261]
Jie, C.; Treyer, V.; Schibli, R.; Mu, L. Tauvid™: The first FDA-approved PET tracer for imaging tau pathology in Alzheimer’s disease. Pharmaceuticals.,  2021, 14(2), 110.
 [http://dx.doi.org/10.3390/ph14020110] [PMID: 33573211]

[262]
Hashimoto, H.; Kawamura, K.; Igarashi, N.; Takei, M.; Fujishiro, T.; Aihara, Y.; Shiomi, S.; Muto, M.; Ito, T.; Furutsuka, K.; Yamasaki, T.; Yui, J.; Xie, L.; Ono, M.; Hatori, A.; Nemoto, K.; Suhara, T.; Higuchi, M.; Zhang, M.R. Radiosynthesis, photoisomerization, biodistribution, and metabolite analysis of 11C-PBB3 as a clinically useful PET probe for imaging of tau pathology. J. Nucl. Med.,  2014, 55(9), 1532-1538.
 [http://dx.doi.org/10.2967/jnumed.114.139550] [PMID: 24963128]

[263]
Maruyama, M.; Shimada, H.; Suhara, T.; Shinotoh, H.; Ji, B.; Maeda, J.; Zhang, M.R.; Trojanowski, J.Q.; Lee, V.M.Y.; Ono, M.; Masamoto, K.; Takano, H.; Sahara, N.; Iwata, N.; Okamura, N.; Furumoto, S.; Kudo, Y.; Chang, Q.; Saido, T.C.; Takashima, A.; Lewis, J.; Jang, M.K.; Aoki, I.; Ito, H.; Higuchi, M. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron,  2013, 79(6), 1094-1108.
 [http://dx.doi.org/10.1016/j.neuron.2013.07.037] [PMID: 24050400]

[264]
World Health Organization.  The top 10 causes of death. Available from: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death (Accessed on: May 12, 2022).

[265]
Go, A.S.; Chertow, G.M.; Fan, D.; McCulloch, C.E.; Hsu, C. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med.,  2004, 351(13), 1296-1305.
 [http://dx.doi.org/10.1056/NEJMoa041031] [PMID: 15385656]

[266]
Sarnak, M.J. Cardiovascular complications in chronic kidney disease. Am. J. Kidney Dis.,  2003, 41(S5), 11-17.
 [http://dx.doi.org/10.1016/S0272-6386(03)00372-X] [PMID: 12776309]

[267]
Zhou, F.; Yu, T.; Du, R.; Fan, G.; Liu, Y.; Liu, Z.; Xiang, J.; Wang, Y.; Song, B.; Gu, X.; Guan, L.; Wei, Y.; Li, H.; Wu, X.; Xu, J.; Tu, S.; Zhang, Y.; Chen, H.; Cao, B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet.,  2020, 395(10229), 1054-1062.
 [http://dx.doi.org/10.1016/S0140-6736(20)30566-3] [PMID: 32171076]

[268]
Shi, S.; Qin, M.; Shen, B.; Cai, Y.; Liu, T.; Yang, F.; Gong, W.; Liu, X.; Liang, J.; Zhao, Q.; Huang, H.; Yang, B.; Huang, C. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiol.,  2020, 5(7), 802-810.
 [http://dx.doi.org/10.1001/jamacardio.2020.0950] [PMID: 32211816]

[269]
Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; Zhao, Y.; Li, Y.; Wang, X.; Peng, Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA,  2020, 323(11), 1061-1069.
 [http://dx.doi.org/10.1001/jama.2020.1585] [PMID: 32031570]

[270]
Kotecha, T.; Knight, D.S.; Razvi, Y.; Kumar, K.; Vimalesvaran, K.; Thornton, G.; Patel, R.; Chacko, L.; Brown, J.T.; Coyle, C.; Leith, D.; Shetye, A.; Ariff, B.; Bell, R.; Captur, G.; Coleman, M.; Goldring, J.; Gopalan, D.; Heightman, M.; Hillman, T.; Howard, L.; Jacobs, M.; Jeetley, P.S.; Kanagaratnam, P.; Kon, O.M.; Lamb, L.E.; Manisty, C.H.; Mathurdas, P.; Mayet, J.; Negus, R.; Patel, N.; Pierce, I.; Russell, G.; Wolff, A.; Xue, H.; Kellman, P.; Moon, J.C.; Treibel, T.A.; Cole, G.D.; Fontana, M. Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance. Eur. Heart J.,  2021, 42(19), 1866-1878.
 [http://dx.doi.org/10.1093/eurheartj/ehab075] [PMID: 33596594]

[271]
Fyhrquist, F.; Saijonmaa, O. Renin-angiotensin system revisited. J. Intern. Med.,  2008, 264(3), 224-236.
 [http://dx.doi.org/10.1111/j.1365-2796.2008.01981.x] [PMID: 18793332]

[272]
Crowley, S.D.; Coffman, T.M. Recent advances involving the renin–angiotensin system. Exp. Cell Res.,  2012, 318(9), 1049-1056.
 [http://dx.doi.org/10.1016/j.yexcr.2012.02.023] [PMID: 22410251]

[273]
de Gasparo, M.; Catt, K.J.; Inagami, T.; Wright, J.W.; Unger, T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol. Rev.,  2000, 52(3), 415-472.
 [PMID: 10977869]

[274]
Karnik, S.S.; Unal, H.; Kemp, J.R.; Tirupula, K.C.; Eguchi, S.; Vanderheyden, P.M.L.; Thomas, W.G. International union of basic and clinical pharmacology. XCIX. Angiotensin receptors: Interpreters of pathophysiological angiotensinergic stimuli. Pharmacol. Rev.,  2015, 67(4), 754-819.
 [http://dx.doi.org/10.1124/pr.114.010454] [PMID: 26315714]

[275]
Miyata, N.; Park, F.; Li, X.F.; Cowley, A.W., Jr Distribution of angiotensin AT1 and AT2 receptor subtypes in the rat kidney. Am. J. Physiol.,  1999, 277(3), F437-F446.
 [PMID: 10484527]

[276]
Allen, A.; Zhuo, J.; Mendelsohn, F.A.O. Localization and function of angiotensin AT1 receptors. Am. J. Hypertens.,  2000, 13(1), S31-S38.
 [http://dx.doi.org/10.1016/S0895-7061(99)00249-6] [PMID: 10678286]

[277]
Smith, R.D.; Chiu, A.T.; Wong, P.C.; Herblin, W.F.; Timmermans, P.B.M.W.M. Pharmacology of nonpeptide angiotensin II receptor antagonists. Annu. Rev. Pharmacol. Toxicol.,  1992, 32(1), 135-165.
 [http://dx.doi.org/10.1146/annurev.pa.32.040192.001031] [PMID: 1605566]

[278]
Timmermans, P.B.; Wong, P.C.; Chiu, A.T.; Herblin, W.F.; Benfield, P.; Carini, D.J.; Lee, R.J.; Wexler, R.R.; Saye, J.A.; Smith, R.D. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol. Rev.,  1993, 45(2), 205-251.
 [PMID: 8372104]

[279]
Chang, R.S.L.; Lotti, V.J. Angiotensin receptor subtypes in rat, rabbit and monkey tissues: Relative distribution and species dependency. Life Sci.,  1991, 49(20), 1485-1490.
 [http://dx.doi.org/10.1016/0024-3205(91)90048-G] [PMID: 1943452]

[280]
Zhu, Y.; Cui, H.; Lv, J.; Liang, H.; Zheng, Y.; Wang, S.; Wang, M.; Wang, H.; Ye, F. AT1 and AT2 receptors modulate renal tubular cell necroptosis in angiotensin II-infused renal injury mice. Sci. Rep.,  2019, 9(1), 19450.
 [http://dx.doi.org/10.1038/s41598-019-55550-8] [PMID: 31857626]

[281]
Unger, T. The role of the renin-angiotensin system in the development of cardiovascular disease. Am. J. Cardiol.,  2002, 89(2), 3-9.
 [http://dx.doi.org/10.1016/S0002-9149(01)02321-9] [PMID: 11835903]

[282]
Jazmín, F.M.; Diego, L.M.; Luisa, M.A. Function of renin angiotensin system on heart failure. J. Integr. Cardiol.,  2016, 2(5), 380-386.
 [http://dx.doi.org/10.15761/JIC.1000180]

[283]
Kim, S.; Iwao, H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol. Rev.,  2000, 52(1), 11-34.
 [PMID: 10699153]

[284]
Billet, S.; Aguilar, F.; Baudry, C.; Clauser, E. Role of angiotensin II AT1 receptor activation in cardiovascular diseases. Kidney Int.,  2008, 74(11), 1379-1384.
 [http://dx.doi.org/10.1038/ki.2008.358] [PMID: 18650793]

[285]
Cong, H.; Li, X.; Ma, L.; Jiang, H.; Mao, Y.; Xu, M.; Angiotensin, I.I. Angiotensin II receptor type 1 is upregulated in atrial tissue of patients with rheumatic valvular disease with atrial fibrillation. J. Thorac. Cardiovasc. Surg.,  2010, 140(2), 298-304.
 [http://dx.doi.org/10.1016/j.jtcvs.2009.10.035] [PMID: 20080265]

[286]
Carey, R.M.; Siragy, H.M. The intrarenal renin–angiotensin system and diabetic nephropathy. Trends Endocrinol. Metab.,  2003, 14(6), 274-281.
 [http://dx.doi.org/10.1016/S1043-2760(03)00111-5] [PMID: 12890592]

[287]
Hisamichi, M.; Kamijo-Ikemori, A.; Sugaya, T.; Ichikawa, D.; Natsuki, T.; Hoshino, S.; Kimura, K.; Shibagaki, Y. Role of angiotensin II type 1a receptor in renal injury induced by deoxycorticosterone acetate–salt hypertension. FASEB J.,  2017, 31(1), 72-84.
 [http://dx.doi.org/10.1096/fj.201600684rr] [PMID: 27663860]

[288]
Pfeffer, M.A.; Swedberg, K.; Granger, C.B.; Held, P.; McMurray, J.J.V.; Michelson, E.L.; Olofsson, B.; Östergren, J.; Yusuf, S.; Pocock, S. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet.,  2003, 362(9386), 759-766.
 [http://dx.doi.org/10.1016/S0140-6736(03)14282-1] [PMID: 13678868]

[289]
Brenner, B.M.; Cooper, M.E.; de Zeeuw, D.; Keane, W.F.; Mitch, W.E.; Parving, H-H.; Remuzzi, G.; Snapinn, S.M.; Zhang, Z.; Shahinfar, S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med.,  2001, 345(12), 861-869.
 [http://dx.doi.org/10.1056/NEJMoa011161]

[290]
Fonarow, G.C.; Yancy, C.W.; Hernandez, A.F.; Peterson, E.D.; Spertus, J.A.; Heidenreich, P.A. Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am. Heart J.,  2011, 161(6), 1024-1030.e3.
 [http://dx.doi.org/10.1016/j.ahj.2011.01.027] [PMID: 21641346]

[291]
Tsoi, B.; Akioyamen, L.E.; Bonner, A.; Frankfurter, C.; Levine, M.; Pullenayegum, E.; Goeree, R.; O’Reilly, D. Comparative efficacy of angiotensin II antagonists in essential hypertension: Systematic review and network meta-analysis of randomised controlled trials. Heart Lung Circ.,  2018, 27(6), 666-682.
 [http://dx.doi.org/10.1016/j.hlc.2017.06.721] [PMID: 28807582]

[292]
Dézsi, C.A. The different therapeutic choices with ARBs. Which one to give? when? why? Am. J. Cardiovasc. Drugs,  2016, 16(4), 255-266.
 [http://dx.doi.org/10.1007/s40256-016-0165-4] [PMID: 26940560]

[293]
Muneer, K.; Nair, A. Angiotensin-converting enzyme inhibitors and receptor blockers in heart failure and chronic kidney disease – Demystifying controversies. Indian Heart J.,  2017, 69(3), 371-374.
 [http://dx.doi.org/10.1016/j.ihj.2016.08.007] [PMID: 28648436]

[294]
Goldberg, A.I.; Dunlay, M.C.; Sweet, C.S. Safety and tolerability of losartan potassium, an angiotensin II receptor antagonist, compared with hydrochlorothiazide, atenolol, felodipne ER, and angiotensin-converting enzyme inhibitors for the treatment of systemic hypertension. Am. J. Cardiol.,  1995, 75(12), 793-795.
 [http://dx.doi.org/10.1016/S0002-9149(99)80413-5] [PMID: 7717281]

[295]
Sidorenkov, G.; Navis, G. Safety of ACE inhibitor therapies in patients with chronic kidney disease. Expert Opin. Drug Saf.,  2014, 13(10), 1383-1395.
 [http://dx.doi.org/10.1517/14740338.2014.951328] [PMID: 25148900]

[296]
Naik, P.; Murumkar, P.; Giridhar, R.; Yadav, M.R.; Angiotensin, I.I. Angiotensin II receptor type 1 (AT1) selective nonpeptidic antagonists—A perspective. Bioorg. Med. Chem.,  2010, 18(24), 8418-8456.
 [http://dx.doi.org/10.1016/j.bmc.2010.10.043] [PMID: 21071232]

[297]
Fierens, F.; Vanderheyden, P.M.L.; De Backer, J.P.; Vauquelin, G. Binding of the antagonist []candesartan to angiotensin II AT1 receptor-tranfected Chinese hamster ovary cells. Eur. J. Pharmacol.,  1999, 367(2-3), 413-422.
 [http://dx.doi.org/10.1016/S0014-2999(98)00965-0] [PMID: 10079018]

[298]
Vanderheyden, P.M.L.; Fierens, F.L.P.; De Backer, J.P.; Fraeyman, N.; Vauquelin, G. Distinction between surmountable and insurmountable selective AT 1 receptor antagonists by use of CHO-K1 cells expressing human angiotensin II AT 1 receptors. Br. J. Pharmacol.,  1999, 126(4), 1057-1065.
 [http://dx.doi.org/10.1038/sj.bjp.0702398] [PMID: 10193788]

[299]
Gibson, R.E.; Beauchamp, H.T.; Fioravanti, C.; Brenner, N.; Burns, H.D. Receptor binding radiotracers for the angiotensin II receptor: Radioiodinated [Sar13,Ile8] angiotensin II. Nucl. Med. Biol.,  1994, 21(4), 593-600.
 [http://dx.doi.org/10.1016/0969-8051(94)90024-8] [PMID: 9234316]

[300]
Verjans, J.W.H.; Lovhaug, D.; Narula, N.; Petrov, A.D.; Indrevoll, B.; Bjurgert, E.; Krasieva, T.B.; Petersen, L.B.; Kindberg, G.M.; Solbakken, M.; Cuthbertson, A.; Vannan, M.A.; Reutelingsperger, C.P.M.; Tromberg, B.J.; Hofstra, L.; Narula, J. Noninvasive imaging of angiotensin receptors after myocardial infarction. JACC Cardiovasc. Imaging,  2008, 1(3), 354-362.
 [http://dx.doi.org/10.1016/j.jcmg.2007.11.007] [PMID: 19356449]

[301]
Amin, A.M.; El-bary, A.A.; El-Mohty, A.A.; Saad, S.M.; El-Sharawy, D.M. Radioiodination and biological evaluation of valsartan as a tracer for cardiovascular disorder detection. Nat. Sci.,  2013, 5(4), 526-531.
 [http://dx.doi.org/10.4236/ns.2013.54066]

[302]
Sanad, M.H.; Sallam, K.M.; Marzook, F.A.; Abd-Elhaliem, S.M. Radioiodination and biological evaluation of candesartan as a tracer for cardiovascular disorder detection. J. Labelled Comp. Radiopharm.,  2016, 59(12), 484-491.
 [http://dx.doi.org/10.1002/jlcr.3435] [PMID: 27634455]

[303]
Sanad, H.M.; Ibrahim, A.A. Radioiodination, diagnostic nuclear imaging and bioevaluation of olmesartan as a tracer for cardiac imaging. Radiochim. Acta,  2018, 106(10), 843-850.
 [http://dx.doi.org/10.1515/ract-2018-2960]

[304]
Sanad, M.H.; Marzook, E.A.; Challan, S.B. Radioiodination of olmesartan medoxomil and biological evaluation of the product as a tracer for cardiac imaging. Radiochim. Acta,  2018, 106(4), 329-336.
 [http://dx.doi.org/10.1515/ract-2017-2830]

[305]
Sanad, M.H.; Marzook, F.A.; Abd-Elhaliem, S.M. Radioiodination and biological evaluation of irbesartan as a tracer for cardiac imaging. Radiochim. Acta,  2021, 109(1), 41-46.
 [http://dx.doi.org/10.1515/ract-2020-0025]

[306]
Santella, J.B., III; Duncia, J.V.; Ensinger, C.L.; VanAtten, M.K.; Carini, D.J.; Wexler, R.R.; Chiu, A.T.; Wong, P.C.; Timmermans, P.B.M.W.M. Balanced angiotensin II receptor antagonists. III. The effects of substitution at the imidazole 5-position. Bioorg. Med. Chem. Lett.,  1994, 4(18), 2235-2240.
 [http://dx.doi.org/10.1016/S0960-894X(00)80077-3]

[307]
Mathews, W.B.; Burns, H.D.; Dannals, R.F.; Ravert, H.T.; Naylor, E.M. Carbon-11 labeling of a potent, nonpeptide, at1-selective angiotensin-II receptor antagonist: MK-996. J. Labelled Comp. Radiopharm.,  1995, 36(8), 729-737.
 [http://dx.doi.org/10.1002/jlcr.2580360804]

[308]
Hamill, T.G.; Donald Burns, H.; Dannals, R.F.; Mathews, W.B.; Musachio, J.L.; Ravert, H.T.; Naylor, E.M. Development of [11C]L-159,884: A radiolabelled, nonpeptide angiotensin II antagonist that is useful for angiotensin II, AT1 receptor imaging. Appl. Radiat. Isot.,  1996, 47(2), 211-218.
 [http://dx.doi.org/10.1016/0969-8043(95)00273-1] [PMID: 8852629]

[309]
Kim, S.E.; Scheffel, U.; Szabo, Z.; Burns, H.D.; Gibson, R.E.; Ravert, H.T.; Mathews, W.B.; Hamill, T.G.; Dannals, R.F. In vivo labeling of angiotensin II receptors with a carbon-11-labeled selective nonpeptide antagonist. J. Nucl. Med.,  1996, 37(2), 307-311.
 [PMID: 8667067]

[310]
Szabo, Z.; Kao, P.F.; Burns, H.D.; Gibson, R.E.; Hamill, T.G.; Ravert, H.T.; Kim, S.E.; Mathews, W.B.; Musachio, J.L.; Scheffel, U.; Dannals, R.F. Investigation of angiotensin II/AT1 receptors with carbon-11-L-159,884: A selective AT1 antagonist. J. Nucl. Med.,  1998, 39(7), 1209-1213.
 [PMID: 9669396]

[311]
Zober, T.G.; Mathews, W.B.; Seckin, E.; Yoo, S.; Hilton, J.; Xia, J.; Sandberg, K.; Ravert, H.T.; Dannals, R.F.; Szabo, Z. PET Imaging of the AT1 receptor with [11C]KR31173. Nucl. Med. Biol.,  2006, 33(1), 5-13.
 [http://dx.doi.org/10.1016/j.nucmedbio.2005.08.005] [PMID: 16459253]

[312]
Szabo, Z.; Speth, R.C.; Brown, P.R.; Kerenyi, L.; Kao, P.F.; Mathews, W.B.; Ravert, H.T.; Hilton, J.; Rauseo, P.; Dannals, R.F.; Zheng, W.; Lee, S.; Sandberg, K. Use of positron emission tomography to study AT1 receptor regulation in vivo. J. Am. Soc. Nephrol.,  2001, 12(7), 1350-1358.
 [http://dx.doi.org/10.1681/ASN.V1271350] [PMID: 11423564]

[313]
Owonikoko, T.K.; Fabucci, M.E.; Brown, P.R.; Nisar, N.; Hilton, J.; Mathews, W.B.; Ravert, H.T.; Rauseo, P.; Sandberg, K.; Dannals, R.F.; Szabo, Z. In vivo investigation of estrogen regulation of adrenal and renal angiotensin (AT1) receptor expression by PET. J. Nucl. Med.,  2004, 45(1), 94-100.
 [PMID: 14734680]

[314]
Mathews, W.B.; Yoo, S.E.; Lee, S.H.; Scheffel, U.; Rauseo, P.A.; Zober, T.G.; Gocco, G.; Sandberg, K.; Ravert, H.T.; Dannals, R.F.; Szabo, Z. A novel radioligand for imaging the AT1 angiotensin receptor with PET. Nucl. Med. Biol.,  2004, 31(5), 571-574.
 [http://dx.doi.org/10.1016/j.nucmedbio.2003.10.014] [PMID: 15219274]

[315]
Ponchant, M.; Demphel, S.; Hinnen, F.; Crouzel, C. Radiosynthesis of [tetrazoyl-11C]irbesartan, a non-peptidic angiotensin II antagonist. Eur. J. Med. Chem.,  1997, 32(9), 747-752.
 [http://dx.doi.org/10.1016/S0223-5234(97)88917-9]

[316]
Mathews, W.B.; Kim, N.J.; Yoo, S.E.; Hilton, J.; Xia, J.; Scheffel, U.; Ravert, H.T.; Dannals, R.F.; Szabo, Z. Synthesis and biodistribution of a radiofluorinated ligand for imaging the AT1 angiotensin receptor with PET. J. Labelled Comp. Radiopharm.,  2007, 50, S308.

[317]
Feng, T.; Tsui, B.M.W.; Li, X.; Vranesic, M.; Lodge, M.A.; Gulaldi, N.C.M.; Szabo, Z. Image-derived and arterial blood sampled input functions for quantitative PET imaging of the angiotensin II subtype 1 receptor in the kidney. Med. Phys.,  2015, 42(11), 6736-6744.
 [http://dx.doi.org/10.1118/1.4934375] [PMID: 26520763]

[318]
Gulaldi, N.C.M.; Xia, J.; Feng, T.; Hong, K.; Mathews, W.B.; Ruben, D.; Kamel, I.R.; Tsui, B.M.W.; Szabo, Z. Modeling of the renal kinetics of the AT1 receptor specific PET radioligand [11C]KR31173. BioMed Res. Int.,  2013, 2013, 1-12.
 [http://dx.doi.org/10.1155/2013/835859] [PMID: 24083243]

[319]
Xia, J.; Seckin, E.; Xiang, Y.; Vranesic, M.; Mathews, W.B.; Hong, K.; Bluemke, D.A.; Lerman, L.O.; Szabo, Z. Positron-emission tomography imaging of the angiotensin II subtype 1 receptor in swine renal artery stenosis. Hypertension,  2008, 51(2), 466-473.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.107.102715] [PMID: 18172054]

[320]
Zober, T.G.; Fabucci, M.E.; Zheng, W.; Brown, P.R.; Seckin, E.; Mathews, W.B.; Sandberg, K.; Szabo, Z. Chronic ACE inhibitor treatment increases angiotensin type 1 receptor binding in vivo in the dog kidney. Eur. J. Nucl. Med. Mol. Imaging,  2008, 35(6), 1109-1116.
 [http://dx.doi.org/10.1007/s00259-007-0667-z] [PMID: 18180920]

[321]
Szabo, Z.; Alachkar, N.; Gulaldi, N.; Vranesic, M.; Chalian, M.; Mathews, W.; Xia, J.; Rabb, H. PET imaging of the angiotensin subtype 1 receptor (AT1R) in human kidney transplants. J. Nucl. Med.,  2010, 51, 427.

[322]
Higuchi, T.; Fukushima, K.; Xia, J.; Mathews, W.B.; Lautamäki, R.; Bravo, P.E.; Javadi, M.S.; Dannals, R.F.; Szabo, Z.; Bengel, F.M. Radionuclide imaging of angiotensin II type 1 receptor upregulation after myocardial ischemia-reperfusion injury. J. Nucl. Med.,  2010, 51(12), 1956-1961.
 [http://dx.doi.org/10.2967/jnumed.110.079855] [PMID: 21078800]

[323]
Fukushima, K.; Bravo, P.E.; Higuchi, T.; Schuleri, K.H.; Lin, X.; Abraham, M.R.; Xia, J.; Mathews, W.B.; Dannals, R.F.; Lardo, A.C.; Szabo, Z.; Bengel, F.M. Molecular hybrid positron emission tomography/computed tomography imaging of cardiac angiotensin II type 1 receptors. J. Am. Coll. Cardiol.,  2012, 60(24), 2527-2534.
 [http://dx.doi.org/10.1016/j.jacc.2012.09.023] [PMID: 23158533]

[324]
Valenta, I.; Szabo, Z.; Mathews, W.B.; Abraham, T.P.; Abraham, M.R.; Schindler, T.H. PET/CT imaging of cardiac angiotensin II Type 1 receptors in nonobstructive hypertrophic cardiomyopathy. JACC Cardiovasc. Imaging,  2019, 12(9), 1895-1896.
 [http://dx.doi.org/10.1016/j.jcmg.2019.03.022] [PMID: 31103588]

[325]
Hadizad, T.; Collins, J.; Antoun, R.E.; Beanlands, R.S.; Dasilva, J.N. [11C]Methyl-losartan as a potential ligand for pet imaging angiotensin II AT1 receptors. J. Labelled Comp. Radiopharm.,  2011, 54, 754-757.
 [http://dx.doi.org/10.1002/jlcr.1917]

[326]
Ismail, B.; Hadizad, T.; Antoun, R.; Lortie, M.; deKemp, R.A.; Beanlands, R.S.B.; DaSilva, J.N. Evaluation of [11C]methyl-losartan and [11C]methyl-EXP3174 for PET imaging of renal AT1receptor in rats. Nucl. Med. Biol.,  2015, 42(11), 850-857.
 [http://dx.doi.org/10.1016/j.nucmedbio.2015.06.012] [PMID: 26300209]

[327]
Hadizad, T.; Kirkpatrick, S.A.; Mason, S.; Burns, K.; Beanlands, R.S.; DaSilva, J.N. Novel O-[11C]methylated derivatives of candesartan as angiotensin II AT1 receptor imaging ligands: Radiosynthesis and ex vivo evaluation in rats. Bioorg. Med. Chem.,  2009, 17(23), 7971-7977.
 [http://dx.doi.org/10.1016/j.bmc.2009.10.016] [PMID: 19879152]

[328]
Lortie, M.; DaSilva, J.N.; Kirkpatrick, S.A.; Hadizad, T.; Ismail, B.A.; Beanlands, R.S.B.; deKemp, R.A. Analysis of [11C]methyl-candesartan kinetics in the rat kidney for the assessment of angiotensin II type 1 receptor density in vivo with PET. Nucl. Med. Biol.,  2013, 40(2), 252-261.
 [http://dx.doi.org/10.1016/j.nucmedbio.2012.10.013] [PMID: 23352346]

[329]
Arksey, N.; Hadizad, T.; Ismail, B.; Hachem, M.; Valdivia, A.C.; Beanlands, R.S.; deKemp, R.A.; DaSilva, J.N. Synthesis and evaluation of the novel 2-[18F]fluoro-3-propoxy-triazole-pyridine-substituted losartan for imaging AT1 receptors. Bioorg. Med. Chem.,  2014, 22(15), 3931-3937.
 [http://dx.doi.org/10.1016/j.bmc.2014.06.011] [PMID: 25023539]

[330]
Hachem, M.; Tiberi, M.; Ismail, B.; Hunter, C.R.; Arksey, N.; Hadizad, T.; Beanlands, R.S.; deKemp, R.A.; DaSilva, J.N. Characterization of 18 F-FPyKYNE-Losartan for Imaging AT1 Receptors. J. Nucl. Med.,  2016, 57(10), 1612-1617.
 [http://dx.doi.org/10.2967/jnumed.115.170951] [PMID: 27199365]

[331]
Ismail, B.; deKemp, R.A.; Hadizad, T.; Mackasey, K.; Beanlands, R.S.; DaSilva, J.N. Decreased renal AT1 receptor binding in rats after subtotal nephrectomy: PET study with [18F]FPyKYNE-losartan. EJNMMI Res.,  2016, 6(1), 55.
 [http://dx.doi.org/10.1186/s13550-016-0209-4] [PMID: 27339045]

[332]
Ismail, B.; deKemp, R.A.; Croteau, E.; Hadizad, T.; Burns, K.D.; Beanlands, R.S.; DaSilva, J.N. Treatment with enalapril and not diltiazem ameliorated progression of chronic kidney disease in rats, and normalized renal AT1 receptor expression as measured with PET imaging. PLoS One,  2017, 12(5), e0177451.
 [http://dx.doi.org/10.1371/journal.pone.0177451] [PMID: 28542215]

[333]
Abreu Diaz, A.M.; Rodriguez Riera, Z.; Lee, Y.; Esteves, L.M.; Normandeau, C.O.; Fezas, B.; Hernandez Saiz, A.; Tournoux, F.; Juneau, D.; DaSilva, J.N. [ 18 F]Fluoropyridine-losartan: A new approach toward human Positron Emission Tomography imaging of Angiotensin II Type 1 receptors. J. Labelled Comp. Radiopharm.,  2023, 66(3), 73-85.
 [http://dx.doi.org/10.1002/jlcr.4014] [PMID: 36656923]

[334]
Chen, X.; Hirano, M.; Werner, R.A.; Decker, M.; Higuchi, T. Novel 18 F-Labeled PET imaging agent FV45 targeting the renin–angiotensin system. ACS Omega,  2018, 3(9), 10460-10470.
 [http://dx.doi.org/10.1021/acsomega.8b01885] [PMID: 30288456]

[335]
Hoffmann, M.; Chen, X.; Hirano, M.; Arimitsu, K.; Kimura, H.; Higuchi, T.; Decker, M. 18 F-labeled derivatives of irbesartan for angiotensin II receptor PET imaging. ChemMedChem.,  2018, 13(23), 2546-2557.
 [http://dx.doi.org/10.1002/cmdc.201800638] [PMID: 30430750]

[336]
Ortega Pijeira, M.S.; Gonçalves Nunes, P.S.; Dos Santos, S.N.; Zhang, Z.; Nario, A.P.; Perini, E.A.; Turato, W.M.; Riera, Z.R.; Chammas, R.; Elsinga, P.H.; Lin, K.S.; Carvalho, I.; Bernardes, E.S. Synthesis and evaluation of [18F]FETLOs and [18F]AMBF3LOS as novel 18F-labelled losartan derivatives for molecular imaging of angiotensin II type 1 receptors. Molecules.,  2020, 25, 1-21.
 [http://dx.doi.org/10.3390/molecules25081872]

[337]
Alonso Martinez, L.M.; DaSilva, J.N. Development of a novel [ 18 F]fluorobenzyl derivative of the AT 1 receptor antagonist Candesartan. J. Labelled Comp. Radiopharm.,  2021, 64(3), 120-128.
 [http://dx.doi.org/10.1002/jlcr.3892] [PMID: 33084079]

[338]
Abreu Diaz, A.M.; Drumeva, G.O.; Laporte, P.; Alonso Martinez, L.M.; Petrenyov, D.R.; Carrier, J.F.; DaSilva, J.N. Evaluation of the high affinity [18F]fluoropyridine-candesartan in rats for PET imaging of renal AT1 receptors. Nucl. Med. Biol.,  2021, 96-97, 41-49.
 [http://dx.doi.org/10.1016/j.nucmedbio.2021.03.003] [PMID: 33798796]

[339]
Abreu Diaz, A.M.; Drumeva, G.O.; Petrenyov, D.R.; Carrier, J.F.; DaSilva, J.N. Synthesis of the novel AT 1 Receptor Tracer [ 18 F]Fluoropyridine–candesartan via click chemistry. ACS Omega,  2020, 5(32), 20353-20362.
 [http://dx.doi.org/10.1021/acsomega.0c02310] [PMID: 32832788]

[340]
Carini, D.J.; Duncia, J.V.; Aldrich, P.E.; Chiu, A.T.; Johnson, A.L.; Pierce, M.E.; Price, W.A.; Santella, J.B., III; Wells, G.J.; Wexler, R.R.; Wong, P.C.; Yoo, S.E.; Timmermans, P.B.M.W.M. Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives. J. Med. Chem.,  1991, 34(8), 2525-2547.
 [http://dx.doi.org/10.1021/jm00112a031] [PMID: 1875348]

[341]
Kubo, K.; Kohara, Y.; Imamiya, E.; Sugiura, Y.; Inada, Y.; Furukawa, Y.; Nishikawa, K.; Naka, T. Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazolecarboxylic acids. J. Med. Chem.,  1993, 36(15), 2182-2195.
 [http://dx.doi.org/10.1021/jm00067a016] [PMID: 8340921]

[342]
Kubo, K.; Inada, Y.; Kohara, Y.; Sugiura, Y.; Ojima, M.; Itoh, K.; Furukawa, Y.; Nishikawa, K.; Naka, T. Nonpeptide angiotensin II receptor antagonists. Synthesis and biological activity of benzimidazoles. J. Med. Chem.,  1993, 36(12), 1772-1784.
 [http://dx.doi.org/10.1021/jm00064a011] [PMID: 8510105]

[343]
Ermert, J.; Neumaier, B. The radiopharmaceutical chemistry of fluorine-18: Nucleophilic fluorinations. In: Radiopharmaceutical Chemistry; Lewis, J.; Windhorst, A.; Zeglis, B., Eds.; Springer: Cham, 2019; pp. 273-283.
 [http://dx.doi.org/10.1007/978-3-319-98947-1_15]

[344]
Chatal, J.F.; Rouzet, F.; Haddad, F.; Bourdeau, C.; Mathieu, C.; Le Guludec, D. Story of rubidium-82 and advantages for myocardial perfusion PET imaging. Front. Med.,  2015, 2, 65.
 [http://dx.doi.org/10.3389/fmed.2015.00065] [PMID: 26442267]

[345]
Brito, A.E.; Etchebehere, E. Radium-223 as an approved modality for treatment of bone metastases. Semin. Nucl. Med.,  2020, 50(2), 177-192.
 [http://dx.doi.org/10.1053/j.semnuclmed.2019.11.005] [PMID: 32172803]

[346]
Sowa, A.R.; Jackson, I.M.; Desmond, T.J.; Alicea, J.; Mufarreh, A.J.; Pham, J.M.; Stauff, J.; Winton, W.P.; Fawaz, M.V.; Henderson, B.D.; Hockley, B.G.; Rogers, V.E.; Koeppe, R.A.; Scott, P.J.H. Futureproofing [18F]Fludeoxyglucose manufacture at an academic medical center. EJNMMI Radiopharm. Chem.,  2018, 3(1), 12.
 [http://dx.doi.org/10.1186/s41181-018-0048-x] [PMID: 30363401]

[347]
Miladinova, D. Molecular imaging in breast cancer. Nucl. Med. Mol. Imaging,  2019, 53(5), 313-319.
 [http://dx.doi.org/10.1007/s13139-019-00614-w] [PMID: 31723360]

[348]
Lu, F.M.; Yuan, Z. PET/SPECT molecular imaging in clinical neuroscience: Recent advances in the investigation of CNS diseases. Quant. Imaging Med. Surg.,  2015, 5(3), 433-447.
 [PMID: 26029646]

[349]
Gomez, J.; Doukky, R.; Germano, G.; Slomka, P. New trends in quantitative nuclear cardiology methods. Curr. Cardiovasc. Imaging Rep.,  2018, 11(1), 1-10.
 [http://dx.doi.org/10.1007/s12410-018-9443-7] [PMID: 30294409]

[350]
Barca, C.; Griessinger, C.; Faust, A.; Depke, D.; Essler, M.; Windhorst, A.; Devoogdt, N.; Brindle, K.; Schäfers, M.; Zinnhardt, B.; Jacobs, A. Expanding theranostic radiopharmaceuticals for tumor diagnosis and therapy. Pharmaceuticals.,  2021, 15(1), 13.
 [http://dx.doi.org/10.3390/ph15010013] [PMID: 35056071]

[351]
Hennrich, U.; Kopka, K. Lutathera®: The first FDA- and EMA-approved radiopharmaceutical for peptide receptor radionuclide therapy. Pharmaceuticals.,  2019, 12(3), 114.
 [http://dx.doi.org/10.3390/ph12030114] [PMID: 31362406]

[352]
Hennrich, U.; Benešová, M. [68Ga]Ga-DOTA-TOC: The first FDA-Approved 68Ga-Radiopharmaceutical for PET imaging. Pharmaceuticals.,  2020, 13(3), 38.
 [http://dx.doi.org/10.3390/ph13030038] [PMID: 32138377]

[353]
Kozempel, J.; Mokhodoeva, O.; Vlk, M. Progress in targeted alpha-particle therapy. What we learned about recoils release from in vivo generators. Molecules,  2018, 23(3), 581.
 [http://dx.doi.org/10.3390/molecules23030581] [PMID: 29510568]

[354]
Holzwarth, U.; Ojea Jimenez, I.; Calzolai, L. A random walk approach to estimate the confinement of α-particle emitters in nanoparticles for targeted radionuclide therapy. EJNMMI Radiopharm. Chem.,  2018, 3(1), 9.
 [http://dx.doi.org/10.1186/s41181-018-0042-3] [PMID: 29888318]

[355]
Mease, R.C.; Kang, C.M.; Kumar, V.; Banerjee, S.R.; Minn, I.; Brummet, M.; Gabrielson, K.L.; Feng, Y.; Park, A.; Kiess, A.P.; Sgouros, G.; Vaidyanathan, G.; Zalutsky, M.R.; Pomper, M.G. An improved 211 At-labeled agent for PSMA-targeted α-therapy. J. Nucl. Med.,  2022, 63(2), 259-267.
 [http://dx.doi.org/10.2967/jnumed.121.262098] [PMID: 34088772]

[356]
Banerjee, S.R.; Minn, I.; Kumar, V.; Josefsson, A.; Lisok, A.; Brummet, M.; Chen, J.; Kiess, A.P.; Baidoo, K.; Brayton, C.; Mease, R.C.; Brechbiel, M.; Sgouros, G.; Hobbs, R.F.; Pomper, M.G. Preclinical evaluation of 203/212 Pb-labeled low-molecular-weight compounds for targeted radiopharmaceutical therapy of prostate cancer. J. Nucl. Med.,  2020, 61(1), 80-88.
 [http://dx.doi.org/10.2967/jnumed.119.229393] [PMID: 31253744]

[357]
Ionetix Produces First Alpha-Emitting Radionuclide at New Isotope Production Facility.  Available from: https://www.prnewswire.com/news-releases/ionetix-produces-first-alpha-emitting-radionuclide-at-new-isotope-production-facility-301799601.html

[358]
Donnelly, D.J. PET imaging in drug discovery and development. In: Handbook of Radiopharmaceuticals; Wiley, 2020; pp. 703-725.
 [http://dx.doi.org/10.1002/9781119500575.ch22]

[359]
Campbell, M.G.; Mercier, J.; Genicot, C.; Gouverneur, V.; Hooker, J.M.; Ritter, T. Bridging the gaps in 18F PET tracer development. Nat. Chem.,  2017, 9(1), 1-3.
 [http://dx.doi.org/10.1038/nchem.2693] [PMID: 27995923]

[360]
Santangelo, P.J.; Rogers, K.A.; Zurla, C.; Blanchard, E.L.; Gumber, S.; Strait, K.; Connor-Stroud, F.; Schuster, D.M.; Amancha, P.K.; Hong, J.J.; Byrareddy, S.N.; Hoxie, J.A.; Vidakovic, B.; Ansari, A.A.; Hunter, E.; Villinger, F. Whole-body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy–treated macaques. Nat. Methods,  2015, 12(5), 427-432.
 [http://dx.doi.org/10.1038/nmeth.3320] [PMID: 25751144]

[361]
Gordon, O.; Ruiz-Bedoya, C.A.; Ordonez, A.A.; Tucker, E.W.; Jain, S.K. Molecular imaging: A novel tool to visualize pathogenesis of infections in situ. MBio,  2019, 10(5), e00317-19.
 [http://dx.doi.org/10.1128/mBio.00317-19] [PMID: 31662452]

[362]
Zhu, A.; Lee, D.; Shim, H. Metabolic positron emission tomography imaging in cancer detection and therapy response. Semin. Oncol.,  2011, 38(1), 55-69.
 [http://dx.doi.org/10.1053/j.seminoncol.2010.11.012] [PMID: 21362516]

[363]
Yang, M.; Sun, J.; Bai, H.X.; Tao, Y.; Tang, X.; States, L.J.; Zhang, Z.; Zhou, J.; Farwell, M.D.; Zhang, P.; Xiao, B.; Yang, L. Diagnostic accuracy of SPECT, PET, and MRS for primary central nervous system lymphoma in HIV patients. Medicine (Baltimore),  2017, 96(19), e6676.
 [http://dx.doi.org/10.1097/MD.0000000000006676] [PMID: 28489744]

[364]
Finnema, S.J.; Nabulsi, N.B.; Eid, T.; Detyniecki, K.; Lin, S.F.; Chen, M.K.; Dhaher, R.; Matuskey, D.; Baum, E.; Holden, D.; Spencer, D.D.; Mercier, J.; Hannestad, J.; Huang, Y.; Carson, R.E. Imaging synaptic density in the living human brain. Sci. Transl. Med.,  2016, 8, 348ra96-348ra96.
 [http://dx.doi.org/10.1126/scitranslmed.aaf6667]

[365]
Onwordi, E.C.; Halff, E.F.; Whitehurst, T.; Mansur, A.; Cotel, M.C.; Wells, L.; Creeney, H.; Bonsall, D.; Rogdaki, M.; Shatalina, E.; Reis Marques, T.; Rabiner, E.A.; Gunn, R.N.; Natesan, S.; Vernon, A.C.; Howes, O.D. Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Nat. Commun.,  2020, 11(1), 246.
 [http://dx.doi.org/10.1038/s41467-019-14122-0] [PMID: 31937764]

[366]
Matthews, P.M.; Rabiner, E.A.; Passchier, J.; Gunn, R.N. Positron emission tomography molecular imaging for drug development. Br. J. Clin. Pharmacol.,  2012, 73(2), 175-186.
 [http://dx.doi.org/10.1111/j.1365-2125.2011.04085.x] [PMID: 21838787]

[367]
Langer, O. Use of PET imaging to evaluate transporter-mediated drug-drug interactions. J. Clin. Pharmacol.,  2016, 56(S7), S143-S156.
 [http://dx.doi.org/10.1002/jcph.722] [PMID: 27385172]
Cite As
Current Medicinal Chemistry

Medicinal (Radio) Chemistry: Building Radiopharmaceuticals for the Future

Abstract
