3-Cyano-4-[F]fluoro-benzoyl-Ala(SOH)-Ala(SOH)-Ava-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH

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.