Backbone metal cyclization: novel 99mTc labeled GnRH analog as potential SPECT molecular imaging agent in cancer.
Gonadotropin-releasing hormone (GnRH) is a decapeptide secreted to the pituitary where it binds to specific receptors on the gonadotropes to regulate gonadotropic hormones (luteinizing hormone (LH) and follicle-stimulating hormone (FSH)) synthesis and secretion. Specific GnRH receptors are overexpressed in breast, prostatic, ovarian, and other tumors. The aim of this study was to synthesize a cyclic GnRH analog with high affinity to GnRH receptors that can be radiolabeled with 99mTc. A precyclic GnRH analog, [Cys-Gly]1[D-Ala]6[N(alpha)(eta-Cys-amino hexyl)]10GnRH (Gn-2), containing two hemi-chelator groups was synthesized. It was cyclized applying the recently reported backbone metal cyclization (BMC) approach, to obtain cyclo(Re(O)1-10)[Cys-Gly]1[D-Ala]6[N(alpha)(eta-Cys-amino hexyl)]10GnRH (cyclo[Re(O)-Gn-2]). For comparative evaluations, Gn-2 was oxidized on-resin to yield cyclo(S-S,1-10)[Cys-Gly]1[D-Ala]6[N(alpha)(eta-Cys-amino hexyl)]10GnRH, (cyclo[S-S-Gn-2]). The binding affinity of cyclo[Re(O)-Gn-2] to rat pituitary membranes showed IC50 of 50 nM, compared to IC50 = 10 nM in the native GnRH. Cyclo(99mTc(O)1-10)[Cys-Gly]1[D-Ala]6[N(alpha)(eta-Cys-amino hexyl)]10GnRH (cyclo[99mTc(O)-Gn-2]) was synthesized from Gn-2 and showed similar chromatographic behavior to its rhenium surrogate.
Department of Organic Chemistry, Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
Yaniv
Y
Barda
Nasi
N
Cohen
Vered
V
Lev
Nurit
N
Ben-Aroya
Yitzhak
Y
Koch
Eyal
E
Mishani
Mati
M
Fridkin
Chaim
C
Gilon
D000818:Animals; D005240:Feasibility Studies; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000737:chemistry* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008670:Metals / Q000737:chemistry; D010902:Pituitary Gland / Q000000981:diagnostic imaging / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics; D051381:Rats; D011920:Rats, Inbred WF; D011966:Receptors, LHRH / Q000737:chemistry* / Q000378:metabolism*; D013667:Technetium / Q000737:chemistry* / Q000493:pharmacokinetics*; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods
D008670:Metals; D019275:Radiopharmaceuticals; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D013667:Technetium