86Y-DOTA-[Pro1,Tyr4]-Bombesin[1-14] (86Y-MP2346) is a peptide analog of human gastrin-releasing peptide (GRP) conjugated with 86Y, and it was developed for positron emission tomography (PET) imaging of tumors with overexpressed GRP receptors (GRP-R) (1). 86Y is a positron emitter with a 33% abundance and a physical half-life (t½) of 14.7 h.
The amphibian bombesin (BBN or BN), a peptide of 14 amino acids, is an analog of human GRP, a peptide of 27 amino acids, that binds to GRP-R with high affinity and specificity (2, 3). Both GRP and BN share an amidated C-terminus sequence homology of 7 amino acids, -Trp-Ala-Val-Gly-His-Leu-Met-NH2. BN-Like peptides have been shown to induce various biological responses in diverse tissues, including the central nervous system (CNS) and the gastrointestinal (GI) system (4, 5). They also act as potential growth factors for both normal and neoplastic tissue. Specific BN receptors (BN-R) have been identified in CNS and GI tissues and a number of tumor cell lines. The BN-R superfamily includes at least 4 different subtypes, namely the GRP-R subtype (BB2), the neuromedin B receptor subtype (BB1), the BB3 subtype, and the BB4 subtype (6). Overexpression of GRP-R in various human tumors (e.g., breast, prostate, lung, colon, ovarian, and pancreatic cancers) provides opportunities to image tumors with the use of specific molecular imaging agents designed to target the GRP-R (1, 3, 7-9).
There have been varying degrees of success in the current development of GRP-R–targeted radiopharmaceuticals for diagnostic or therapeutic applications (9). Various BN analogs have been labeled with 99mTc and 111In for single-photon emission computed tomography (SPECT) imaging (10, 11). BN Analogs labeled with 68Ga, 18F, or 64Cu have been studied for PET imaging (1, 12, 13). Breeman et al. (14, 15) prepared two GRP-R agonists, diethylene triamine pentaacetic acid (DTPA)-[Pro1,Tyr4]BN[1-14] and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-[Pro1,Tyr4]BN[1-14] (MP2346), for radiometal labeling by replacing pGlu1 and Leu4 in the native BN with DTPA-Pro or DOTA-Pro and with Tyr, respectively. Both MP2346 and DTPA-[Pro1,Tyr4]BN[1-14] were readily labeled with 111In and appeared to be promising radioligands for SPECT imaging. For PET imaging, Biddlecombe et al. (1) prepared and evaluated 86Y-MP2346 because yttrium-DTPA–conjugated peptides are not stable in vivo (15). In comparison with 64Cu-MP2346. Biddlecombe et al. (1) reported distinct differences in the in vivo pharmacokinetics and tumor uptake of these two radioligands. The authors suggested that this may be the result of their differences in peptide to receptor affinity, overall chemical charge, and radiometal-chelate stability.