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Current Radiopharmaceuticals

Author(s): Farzaneh Rezazadeh, Sara Karoubian, Saied Abediankenari, Nourollah Sadeghzadeh*, Manouchehr Jandaghi and Shayan Rasuli

DOI: 10.2174/1874471013666200604175905

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The Effects of the Spacer on Radiochemical and Biological Properties of New Radiolabeled Bombesin(7-14) Derivative

Page: [149 - 158] Pages: 10

  • * (Excluding Mailing and Handling)

Abstract

Objective: The aim of this study was to develop 99mTc-[HYNIC-X-D-Phe13]-BBN(7-14)NH2 derivatives using two different tripeptidic spacer groups (X=GGG and X=SSS) in order to improve its pharmacokinetics, in vitro stability, specific binding, and affinity.

Background: Bombesin (BBN), a 14-aminoacid amphibian peptide homolog of mammalian gastrinreleasing peptide (GRP), has demonstrated the ability to bind with high affinity and specificity to GRP receptor, which is overexpressed on a variety of human cancers.

Methods: Peptide conjugates labeled with 99mTc using tricine-EDDA and radiochemical purity was assessed by TLC and HPLC. The stability of radio conjugates was evaluated in the presence of saline and human serum. Affinity, internalization, and also dissociation Constant was evaluated using MDAMB- 231 and PC-3 cell line. Biodistribution study was performed in BALB/C mice.

Results: Labeling yield of ˃95% was obtained. The change introduced in the BBN sequence increased plasma stability. In vitro blocking studies showed that binding and internalization of both radiolabeled peptides are mediated by their receptors on the surface of MDA-MB-231 and PC-3 cells. Biodistribution results demonstrated a rapid blood clearance, with predominantly renal excretion. Specific binding in GRP receptor-positive tissues, such as pancreas was confirmed with a blocking study.

Conclusion: The introduction of the spacer sequence between chelator and BBN(7-14) led to improved bidistribution. Analog with tri-Gly spacer is the more promising radiopeptide for targeting GRP receptors than Ser conjugates.

Therefore, these analogs can be considered as a candidate for the identification of bombesin-positive tumors.

Keywords: Bombesin, GRP, cancer, spacer, 99mTc, tumor, cell lines, radiochemical.

Graphical Abstract

[1]
Van Den Bossche, B.; Van de Wiele, C. Receptor imaging in oncology by means of nuclear medicine: current status. J. Clin. Oncol., 2004, 22(17), 3593-3607.
[http://dx.doi.org/10.1200/JCO.2004.10.216] [PMID: 15337810]
[2]
Reubi, J.C. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr. Rev., 2003, 24(4), 389-427.
[http://dx.doi.org/10.1210/er.2002-0007] [PMID: 12920149]
[3]
Okarvi, S.M. Peptide-based radiopharmaceuticals: future tools for diagnostic imaging of cancers and other diseases. Med. Res. Rev., 2004, 24(3), 357-397.
[http://dx.doi.org/10.1002/med.20002] [PMID: 14994368]
[4]
Anastasi, A.; Erspamer, V.; Bucci, M. Isolation and amino acid sequences of alytesin and bombesin, two analogous active tetradecapeptides from the skin of European discoglossid frogs. Arch. Biochem. Biophys., 1972, 148(2), 443-446.
[http://dx.doi.org/10.1016/0003-9861(72)90162-2] [PMID: 4537042]
[5]
McDonald, T.J.; Jörnvall, H.; Nilsson, G.; Vagne, M.; Ghatei, M.; Bloom, S.R.; Mutt, V. Characterization of a gastrin releasing peptide from porcine non-antral gastric tissue. Biochem. Biophys. Res. Commun., 1979, 90(1), 227-233.
[http://dx.doi.org/10.1016/0006-291X(79)91614-0] [PMID: 496973]
[6]
Gugger, M.; Reubi, J.C. Gastrin-releasing peptide receptors in non-neoplastic and neoplastic human breast. Am. J. Pathol., 1999, 155(6), 2067-2076.
[http://dx.doi.org/10.1016/S0002-9440(10)65525-3] [PMID: 10595936]
[7]
Markwalder, R.; Reubi, J.C. Gastrin-releasing peptide receptors in the human prostate: relation to neoplastic transformation. Cancer Res., 1999, 59(5), 1152-1159.
[PMID: 10070977]
[8]
Hoffman, T.J.; Quinn, T.P.; Volkert, W.A. Radiometallated receptor-avid peptide conjugates for specific in vivo targeting of cancer cells. Nucl. Med. Biol., 2001, 28(5), 527-539.
[http://dx.doi.org/10.1016/S0969-8051(01)00209-8] [PMID: 11516698]
[9]
Moody, T.W.; Crawley, J.N.; Jensen, R.T. Pharmacology and neurochemistry of bombesin-like peptides. Peptides, 1982, 3(3), 559-563.
[http://dx.doi.org/10.1016/0196-9781(82)90126-7] [PMID: 6181494]
[10]
Rezazadeh, F.; Sadeghzadeh, N. Tumor targeting with 99m Tc radiolabeled peptides: Clinical application and recent development. Chem. Biol. Drug Des., 2019, 93(3), 205-221.
[http://dx.doi.org/10.1111/cbdd.13413] [PMID: 30299570]
[11]
Liu, S.; Edwards, D.S. 99mTc-labeled small peptides as diagnostic radiopharmaceuticals. Chem. Rev., 1999, 99(9), 2235-2268.
[http://dx.doi.org/10.1021/cr980436l] [PMID: 11749481]
[12]
Mantey, S.A.; Weber, H.C.; Sainz, E.; Akeson, M.; Ryan, R.R.; Pradhan, T.K.; Searles, R.P.; Spindel, E.R.; Battey, J.F.; Coy, D.H.; Jensen, R.T. Discovery of a high affinity radioligand for the human orphan receptor, bombesin receptor subtype 3, which demonstrates that it has a unique pharmacology compared with other mammalian bombesin receptors. J. Biol. Chem., 1997, 272(41), 26062-26071.
[http://dx.doi.org/10.1074/jbc.272.41.26062] [PMID: 9325344]
[13]
Moody, T.W.; Mantey, S.A.; Pradhan, T.K.; Schumann, M.; Nakagawa, T.; Martinez, A.; Fuselier, J.; Coy, D.H.; Jensen, R.T. Development of high affinity camptothecin-bombesin conjugates that have targeted cytotoxicity for bombesin receptor-containing tumor cells. J. Biol. Chem., 2004, 279(22), 23580-23589.
[http://dx.doi.org/10.1074/jbc.M401938200] [PMID: 15016826]
[14]
Okarvi, S.M.; Jammaz, I.A. Preparation and evaluation of bombesin peptide derivatives as potential tumor imaging agents: effects of structure and composition of amino acid sequence on in vitro and in vivo characteristics. Nucl. Med. Biol., 2012, 39(6), 795-804.
[http://dx.doi.org/10.1016/j.nucmedbio.2012.01.002] [PMID: 22381782]
[15]
Sadeghzadeh, N.; Ahmadzadeh, M.; Erfani, M. Evaluation of a new radiolabeled bombesin derivative with 99mTc as potential targeted tumor imaging agent. J. Radioanal. Nucl. Chem., 2013, 298(1), 287-293.
[http://dx.doi.org/10.1007/s10967-013-2464-4] [PMID: 26224936]
[16]
Shipp, M.A.; Tarr, G.E.; Chen, C.Y.; Switzer, S.N.; Hersh, L.B.; Stein, H.; Sunday, M.E.; Reinherz, E.L. CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung. Proc. Natl. Acad. Sci. USA, 1991, 88(23), 10662-10666.
[http://dx.doi.org/10.1073/pnas.88.23.10662] [PMID: 1660144]
[17]
Linder, K.E.; Metcalfe, E.; Arunachalam, T.; Chen, J.; Eaton, S.M.; Feng, W.; Fan, H.; Raju, N.; Cagnolini, A.; Lantry, L.E.; Nunn, A.D.; Swenson, R.E. In vitro and in vivo metabolism of Lu-AMBA, a GRP-receptor binding compound, and the synthesis and characterization of its metabolites. Bioconjug. Chem., 2009, 20(6), 1171-1178.
[http://dx.doi.org/10.1021/bc9000189] [PMID: 19480415]
[18]
Van de Wiele, C.; Dumont, F.; Dierckx, R.A.; Peers, S.H.; Thornback, J.R.; Slegers, G.; Thierens, H. Biodistribution and dosimetry of (99m)Tc-RP527, a gastrin-releasing peptide (GRP) agonist for the visualization of GRP receptor-expressing malignancies. J. Nucl. Med., 2001, 42(11), 1722-1727.
[PMID: 11696645]
[19]
Hoffman, T.J.; Gali, H.; Smith, C.J.; Sieckman, G.L.; Hayes, D.L.; Owen, N.K.; Volkert, W.A. Novel series of 111In-labeled bombesin analogs as potential radiopharmaceuticals for specific targeting of gastrin-releasing peptide receptors expressed on human prostate cancer cells. J. Nucl. Med., 2003, 44(5), 823-831.
[PMID: 12732685]
[20]
Prasanphanich, A.F.; Lane, S.R.; Figueroa, S.D.; Ma, L.; Rold, T.L.; Sieckman, G.L.; Hoffman, T.J.; McCrate, J.M.; Smith, C.J. The effects of linking substituents on the in vivo behavior of site-directed, peptide-based, diagnostic radiopharmaceuticals. In Vivo, 2007, 21(1), 1-16.
[PMID: 17354608]
[21]
Sadeghzadeh, N. Radiochemical Evaluation of New 99mTc-labelled Bombesin Derivatives with Tripeptidic (Ser-Ser-Ser) and (Gly-Gly-Gly) Spacer for Targeting GRP Receptor Positive-tumors. Majallah-i Danishgah-i Ulum-i Pizishki-i Mazandaran, 2015, 25(129), 70-80.
[22]
Nock, B.A.; Nikolopoulou, A.; Galanis, A.; Cordopatis, P.; Waser, B.; Reubi, J.C.; Maina, T. Potent bombesin-like peptides for GRP-receptor targeting of tumors with 99mTc: a preclinical study. J. Med. Chem., 2005, 48(1), 100-110.
[http://dx.doi.org/10.1021/jm049437y] [PMID: 15634004]
[23]
Bauer, R.; Pabst, H-W. Tc-generators - yield of 99mTc and ratio to ‘inactive’ 99Tc. Eur. J. Nucl. Med., 1982, 7(1), 35-36.
[http://dx.doi.org/10.1007/BF00275242] [PMID: 7060601]
[24]
Elias, D.R.; Thorek, D.L.; Chen, A.K.; Czupryna, J.; Tsourkas, A. In vivo imaging of cancer biomarkers using activatable molecular probes. Cancer Biomark., 2008, 4(6), 287-305.
[http://dx.doi.org/10.3233/CBM-2008-4602] [PMID: 19126958]
[25]
Shirmardi, S.P.; Gandomkar, M.; Maragheh, M.G.; Shamsaei, M. Preclinical evaluation of a new bombesin analog for imaging of gastrin-releasing peptide receptors. Cancer Biother. Radiopharm., 2011, 26(3), 309-316.
[http://dx.doi.org/10.1089/cbr.2010.0912] [PMID: 21711115]
[26]
Breeman, W.A.; Hofland, L.J.; de Jong, M.; Bernard, B.F.; Srinivasan, A.; Kwekkeboom, D.J.; Visser, T.J.; Krenning, E.P. Evaluation of radiolabelled bombesin analogues for receptor-targeted scintigraphy and radiotherapy. Int. J. Cancer, 1999, 81(4), 658-665.
[http://dx.doi.org/10.1002/(SICI)1097-0215(19990517)81:4<658:AID-IJC24>3.0.CO;2-P] [PMID: 10225459]
[27]
Smith, C.J.; Volkert, W.A.; Hoffman, T.J. Gastrin releasing peptide (GRP) receptor targeted radiopharmaceuticals: a concise update. Nucl. Med. Biol., 2003, 30(8), 861-868.
[http://dx.doi.org/10.1016/S0969-8051(03)00116-1] [PMID: 14698790]
[28]
Chen, X.; Park, R.; Hou, Y.; Tohme, M.; Shahinian, A.H.; Bading, J.R.; Conti, P.S. microPET and autoradiographic imaging of GRP receptor expression with 64Cu-DOTA-[Lys3]bombesin in human prostate adenocarcinoma xenografts. J. Nucl. Med., 2004, 45(8), 1390-1397.
[PMID: 15299066]
[29]
Smith, C.J.; Gali, H.; Sieckman, G.L.; Higginbotham, C.; Volkert, W.A.; Hoffman, T.J. Radiochemical investigations of (99m)Tc-N(3)S-X-BBN[7-14]NH(2): an in vitro/in vivo structure-activity relationship study where X = 0-, 3-, 5-, 8-, and 11-carbon tethering moieties. Bioconjug. Chem., 2003, 14(1), 93-102.
[http://dx.doi.org/10.1021/bc020034r] [PMID: 12526698]
[30]
Pujatti, P.B.; Santos, J.S.; Massicano, A.V.; Mengatti, J.; De Araújo, E.B. Development of a new bombesin analog radiolabeled with lutetium-177: in vivo evaluation of the biological properties in Balb-C mice. Cell. Mol. Biol., 2010, 56(2), 18-24.
[PMID: 20525454]
[31]
Alves, S.; Correia, J.D.; Santos, I.; Veerendra, B.; Sieckman, G.L.; Hoffman, T.J.; Rold, T.L.; Figueroa, S.D.; Retzloff, L.; McCrate, J.; Prasanphanich, A.; Smith, C.J. Pyrazolyl conjugates of bombesin: a new tridentate ligand framework for the stabilization of fac-[M(CO)3] moiety. Nucl. Med. Biol., 2006, 33(5), 625-634.
[http://dx.doi.org/10.1016/j.nucmedbio.2006.03.007] [PMID: 16843837]
[32]
Parry, J.J.; Kelly, T.S.; Andrews, R.; Rogers, B.E. In vitro and in vivo evaluation of 64Cu-labeled DOTA-linker-bombesin(7-14) analogues containing different amino acid linker moieties. Bioconjug. Chem., 2007, 18(4), 1110-1117.
[http://dx.doi.org/10.1021/bc0603788] [PMID: 17503761]
[33]
Decristoforo, C.; Mather, S.J. 99m-Technetium-labelled peptide-HYNIC conjugates: effects of lipophilicity and stability on biodistribution. Nucl. Med. Biol., 1999, 26(4), 389-396.
[http://dx.doi.org/10.1016/S0969-8051(98)00118-8] [PMID: 10382842]
[34]
Däpp, S.; García Garayoa, E.; Maes, V.; Brans, L.; Tourwé, D.A.; Müller, C.; Schibli, R. PEGylation of (99m)Tc-labeled bombesin analogues improves their pharmacokinetic properties. Nucl. Med. Biol., 2011, 38(7), 997-1009.
[http://dx.doi.org/10.1016/j.nucmedbio.2011.02.014] [PMID: 21982571]
[35]
La Bella, R.; Garcia-Garayoa, E.; Langer, M.; Bläuenstein, P.; Beck-Sickinger, A.G.; Schubiger, P.A. In vitro and in vivo evaluation of a 99mTc(I)-labeled bombesin analogue for imaging of gastrin releasing peptide receptor-positive tumors. Nucl. Med. Biol., 2002, 29(5), 553-560.
[http://dx.doi.org/10.1016/S0969-8051(02)00314-1] [PMID: 12088725]
[36]
Smith, C.J.; Sieckman, G.L.; Owen, N.K.; Hayes, D.L.; Mazuru, D.G.; Volkert, W.A.; Hoffman, T.J. Radiochemical investigations of [188Re(H2O)(CO)3-diaminopropionic acid-SSS-bombesin(7-14)NH2]: syntheses, radiolabeling and in vitro/in vivo GRP receptor targeting studies. Anticancer Res., 2003, 23(1A), 63-70.
[PMID: 12680195]
[37]
Baidoo, K.E.; Lin, K.S.; Zhan, Y.; Finley, P.; Scheffel, U.; Wagner, H.N. Jr Design, synthesis, and initial evaluation of high-affinity technetium bombesin analogues. Bioconjug. Chem., 1998, 9(2), 218-225.
[http://dx.doi.org/10.1021/bc9701959] [PMID: 9548537]