Gastrin Releasing Peptide Receptor-Directed Radioligands Based on a Bombesin Antagonist: Synthesis, In-111-Labeling, and Preclinical Profile

Novel bombesin (BBN) antagonists were synthesized by coupling the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) to H-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (JMV594) through linkers of increasing number of (beta Ala)(x) residues (x = 1-3). Labeling with In-111 afforded the respective radiotracers in high purity and high specific activity. Bioconjugate affinity for the gastrin releasing peptide receptor (GRPR) as determined against [I-125-Tyr(4)]BBN was high (IC50 values in the lower nanomolar range). Radioligands poorly internalized in PC-3 cells at 37 degrees C. Radiopeptides remained >60% intact 5 min after entering the bloodstream of healthy mice. After injection in SCID mice bearing human PC-3 xenografts all analogues showed high tumor uptake and rapid background clearance via the kidneys into urine. Interestingly, pancreatic uptake, albeit GRPR-specific, declined rapidly with time. In-111-DOTA-(beta Ala)(2)-JMV594 achieved the highest tumor values among the group (17.0 +/- 2.8%ID/g vs. 8-10%ID/g, respectively, at 4 h pi) indicating that the (beta Ala)(2)-linker favors in vivo interaction of radiopeptides with the GRPR.