title: Synthesis and evaluation of novel gonadotropin-releasing hormone receptor-targeting peptides.
abstract: The purpose of this study was to develop novel radiolabeled gonadotropin-releasing hormone (GnRH) receptor-targeting peptides for breast cancer imaging. Three novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated GnRH peptides were designed and synthesized. The radiometal chelator DOTA was conjugated to the epsilon or alpha amino group of D-lysine, or the epsilon amino group of L-lysine via an Ahx {aminohexanoic acid} linker to generate DOTA-Ahx-(D-Lys(6)-GnRH1), DOTA-Ahx-(D-Lys(6)-GnRH2) and DOTA-Ahx-(L-Lys(6)-GnRH3), respectively. The conjugation of the DOTA to the epsilon amino group of D-lysine (rather than alpha amino group of D-lysine nor epsilon amino group of L-lysine) maintained the nanomolar GnRH receptor binding affinity. The IC(50) values of DOTA-Ahx-(D-Lys(6)-GnRH1), DOTA-Ahx-(D-Lys(6)-GnRH2) and DOTA-Ahx-(L-Lys(6)-GnRH3) were 36.1 nM, 10.6 mM and 4.3 mM, respectively. Since only DOTA-Ahx-(D-Lys(6)-GnRH1) displayed nanomolar receptor binding affinity, the specific GnRH receptor binding of (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1) was determined in human GnRH receptor membrane preparations. Furthermore, the biodistribution and tumor imaging properties of (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1) were examined in MDA-MB-231 human breast cancer-xenografted nude mice. (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1) exhibited specific GnRH receptor binding and rapid tumor uptake (1.76 ± 0.58% ID/g at 0.5 h postinjection) coupled with fast whole-body clearance through the urinary system. The MDA-MB-231 human breast cancer-xenografted tumor lesions were clearly visualized by single photon emission computed tomography (SPECT)/CT at 1 h postinjection of (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1). The profound impact of DOTA position on the binding affinity of the GnRH peptide provided a new insight into the design of novel radiolabeled GnRH peptides. The successful imaging of MDA-MB-231 human breast cancer-xenografted tumor lesions using (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1) suggested its potential as a novel imaging probe for human breast cancer imaging.
authors: College of Pharmacy, University of New Mexico, Albuquerque, New Mexico 87131, United States.
authors: Haixun
authors: H
authors: Guo
authors: Jie
authors: J
authors: Lu
authors: Helen
authors: H
authors: Hathaway
authors: Melanie E
authors: ME
authors: Royce
authors: Eric R
authors: ER
authors: Prossnitz
authors: Yubin
authors: Y
authors: Miao
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000175:diagnosis / Q000000981:diagnostic imaging* / Q000473:pathology; D003952:Diagnostic Imaging / Q000379:methods; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D019275:Radiopharmaceuticals / Q000138:chemical synthesis; D011966:Receptors, LHRH / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods; D014183:Transplantation, Heterologous
chemical_list: C484844:GNRHR protein, human; D007205:Indium Radioisotopes; D010455:Peptides; D019275:Radiopharmaceuticals; D011966:Receptors, LHRH