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 Tc-99m. A precyclic GnRH analog, [Cys-Gly](1) [DAla](6)[N-alpha(eta-Cys-amino hexyl)](10) GnRH (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)](10) GnRH (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-Cysamino hexyl)](10) GnRH, (cyclo[S-S-Gn-2]). The binding affinity of cyclo[Re(O)-Gn-2] to rat pituitary membranes showed IC50 of 50nM, compared to IC50 = 10 nM in the native GnRH. Cyclo(Tc-99m(O)1-10)[Cys-Gly](1)[D-Ala](6)[N-alpha (eta-Cys-amino hexyl)](10) GnRH (cyclo[Tc-99m(O)-Gn-2]) was synthesized from Gn-2 and showed similar chromatographic behavior to its rhenium surrogate. (C) 2004 Elsevier Inc. All rights reserved.