Leung Kam
National Center for Biotechnology Information, NLM, NIH
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), which binds to the 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, as well as on a number of tumor cell lines. The BBN-receptor superfamily includes at least four different subtypes: 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 because antagonists usually bind to both high and low affinity sites of the target receptor and agonists only bind to high affinity sites. 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 imaging agent for GRPR, RM1 has been labeled with In 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 Ga for positron emission tomography (PET) imaging (6). 3-Cyano-4-[F]fluoro-benzoyl-Ala(SOH)-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH ([F]7b) was reported to have high prostate tumor accumulation (7). To increase the hydrophilicity of this agent, Honer et al. (8) inserted one more Ala(SOH) moiety in the linker of [F]7b to form 3-cyano-4-[F]fluoro-benzoyl-Ala(SOH)-Ala(SOH)-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH ([F]BAY 86-4367). [F]BAY 86-4367 showed specific and effective tumor targeting in prostate cancer xenografts in nude mice.
两栖类蛙皮素（BBN 或 BN，一种 14 个氨基酸的肽）是人类胃泌素释放肽（GRP，一种 27 个氨基酸的肽）的类似物，它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。它们还作为正常组织和肿瘤组织的潜在生长因子发挥作用（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：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，因为拮抗剂通常与靶受体的高亲和力和低亲和力位点都结合，而激动剂只与高亲和力位点结合。利纳雷斯等人（4）开发了一系列 GRPR 肽拮抗剂。其中之一，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，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成像剂，RM1 已用¹¹¹In 标记形成¹¹¹In - RM1（5）。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），已被发现对 GRPR 的亲和力比 RM1 更高，并已用⁶⁸Ga 标记用于正电子发射断层扫描（PET）成像（6）。3 - 氰基 - 4 - [¹⁸F]氟 - 苯甲酰基 - Ala(SO₃H) - Ava - Gln - Trp - Ala - Val - NMeGly - His - Sta - Leu - NH₂（[¹⁸F]7b）据报道在前列腺肿瘤中具有高积聚性（7）。为了增加这种试剂的亲水性，霍纳等人（8）在[¹⁸F]7b 的连接子中再插入一个 Ala(SO₃H)部分，形成 3 - 氰基 - 4 - [¹⁸F]氟 - 苯甲酰基 - Ala(SO₃H) - Ala(SO₃H) - Ava - Gln - Trp - Ala - Val - NMeGly - His - Sta - Leu - NH₂（[¹⁸F]BAY 86 - 4367）。[¹⁸F]BAY 86 - 4367 在裸鼠前列腺癌异种移植模型中显示出特异性和有效的肿瘤靶向性。
