Barda Yaniv, Cohen Nasi, Lev Vered, Ben-Aroya Nurit, Koch Yitzhak, Mishani Eyal, Fridkin Mati, Gilon Chaim
Department of Organic Chemistry, Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
Nucl Med Biol. 2004 Oct;31(7):921-33. doi: 10.1016/j.nucmedbio.2004.05.003.
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.
促性腺激素释放激素（GnRH）是一种十肽，分泌至垂体后与促性腺激素细胞上的特异性受体结合，从而调节促性腺激素（黄体生成素（LH）和卵泡刺激素（FSH））的合成与分泌。特异性GnRH受体在乳腺、前列腺、卵巢及其他肿瘤中过表达。本研究的目的是合成一种对GnRH受体具有高亲和力且可被99mTc放射性标记的环状GnRH类似物。合成了一种含有两个半螯合剂基团的前环GnRH类似物，即[Cys-Gly]1[D-Ala]6[N(α)(η-Cys-氨基己基)]10GnRH（Gn-2）。采用最近报道的主链金属环化（BMC）方法将其环化，得到环(Re(O)1-10)[Cys-Gly]1[D-Ala]6[N(α)(η-Cys-氨基己基)]10GnRH（环[Re(O)-Gn-2]）。为进行比较评估，在树脂上氧化Gn-2以产生环(S-S,1-10)[Cys-Gly]1[D-Ala]6[N(α)(η-Cys-氨基己基)]10GnRH（环[S-S-Gn-2]）。环[Re(O)-Gn-2]对大鼠垂体膜的结合亲和力显示IC50为50 nM，而天然GnRH的IC50 = 10 nM。由Gn-2合成了环(99mTc(O)1-10)[Cys-Gly]1[D-Ala]6[N(α)(η-Cys-氨基己基)]10GnRH（环[99mTc(O)-Gn-2]），其色谱行为与其铼替代物相似。
