主链金属环化：新型99mTc标记的促性腺激素释放激素类似物作为癌症潜在的单光子发射计算机断层扫描分子成像剂。

Backbone metal cyclization: novel 99mTc labeled GnRH analog as potential SPECT molecular imaging agent in cancer.

作者信息

Barda Yaniv, Cohen Nasi, Lev Vered, Ben-Aroya Nurit, Koch Yitzhak, Mishani Eyal, Fridkin Mati, Gilon Chaim

机构信息

Department of Organic Chemistry, Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, 91904, Israel.

出版信息

Nucl Med Biol. 2004 Oct;31(7):921-33. doi: 10.1016/j.nucmedbio.2004.05.003.

DOI:10.1016/j.nucmedbio.2004.05.003

PMID:15464394

Abstract

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.

摘要

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。