铟-四氮杂环十二烷四乙酸-4-氨基-1-羧甲基-哌啶-D-苯丙氨酸-谷氨酰胺-色氨酸-丙氨酸-缬氨酸-甘氨酸-组氨酸-司他丁-亮氨酸-酰胺

In-DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH

作者信息

Leung Kam

机构信息

National Center for Biotechnology Information, NLM, NIH

Abstract

The amphibian bombesin (BBN or BN, a peptide of 14 amino acids) is an analog of human gastrin-releasing peptide (GRP, a peptide of 27 amino acids) that binds to GRP receptor (GRPR) with high affinity and specificity (1). Both GRP and BBN share an amidated C-terminus sequence homology of seven amino acids, Trp-Ala-Val-Gly-His-Leu-Met-NH. BBN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system (CNS) and the gastrointestinal (GI) system. They also act as potential growth factors for both normal and neoplastic tissues (2). Specific BBN receptors have been identified on CNS and GI tissues, including the pancreas, and on a number of tumor cell lines. The BBN-receptor superfamily includes at least four different subtypes, namely neuromedin B (NMB or BB1), the GRPR subtype (BB2), the BB3 subtype, and the BB4 subtype (3). The findings of GRPR overexpression in various human tumors, such as breast, prostate, lung, colon, ovarian, and pancreatic cancers, provide opportunities for tumor imaging by designing specific molecular imaging agents to target the GRPR. Currently used targeting GRPR peptides are primarily agonists. Therefore, there is a need for GRPR antagonist radioligands. Llinares et al. (4) developed a series of GRPR peptide antagonists. One of them, d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH (RM26), has been found to be a selective GRPR antagonist. A DOTA-Gly-benzoyl group was added to the C-terminus to form DOTA-Gly-benzoyl-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH (RM1). For evaluation as a single-photon emission computed tomography (SPECT) imaging agent for GRPR, In has been attached to RM1 to form In-RM1 (5). A new GRPR peptide antagonist, DOTA-4-amino-1-carboxymethyl-piperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH (RM2), has been found to have a higher affinity for GRPR than RM1 and has been labeled with In for single-photon emission computed tomography (SPECT) imaging (6).

摘要

两栖类蛙皮素（BBN 或 BN，一种由 14 个氨基酸组成的肽）是人类胃泌素释放肽（GRP，一种由 27 个氨基酸组成的肽）的类似物，它能以高亲和力和特异性与 GRP 受体（GRPR）结合（1）。GRP 和 BBN 都有一个由七个氨基酸组成的酰胺化 C 末端序列同源性，即 Trp-Ala-Val-Gly-His-Leu-Met-NH₂。已证明类 BBN 肽能在包括中枢神经系统（CNS）和胃肠道（GI）系统在内的多种组织中诱导各种生物学反应。它们还可作为正常组织和肿瘤组织的潜在生长因子（2）。在 CNS 和 GI 组织（包括胰腺）以及许多肿瘤细胞系上已鉴定出特异性的 BBN 受体。BBN 受体超家族至少包括四种不同的亚型，即神经介素 B（NMB 或 BB1）、GRPR 亚型（BB2）、BB3 亚型和 BB4 亚型（3）。在各种人类肿瘤（如乳腺癌、前列腺癌、肺癌、结肠癌、卵巢癌和胰腺癌）中发现 GRPR 过表达，这为通过设计靶向 GRPR 的特异性分子成像剂进行肿瘤成像提供了机会。目前使用的靶向 GRPR 的肽主要是激动剂。因此，需要 GRPR 拮抗剂放射性配体。利纳雷斯等人（4）开发了一系列 GRPR 肽拮抗剂。其中一种，d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂（RM26），已被发现是一种选择性 GRPR 拮抗剂。在 C 末端添加了一个 DOTA-Gly-苯甲酰基以形成 DOTA-Gly-苯甲酰基-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂（RM1）。为了评估其作为 GRPR 的单光子发射计算机断层扫描（SPECT）成像剂，已将¹¹¹In 连接到 RM1 上以形成¹¹¹In-RM1（5）。已发现一种新的 GRPR 肽拮抗剂，DOTA-4-氨基-1-羧甲基-哌啶-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH₂（RM2），对 GRPR 的亲和力高于 RM1，并已用¹¹¹In 标记用于单光子发射计算机断层扫描（SPECT）成像（6）。