Radiopeptide antagonists for imaging and therapy of GRPR⁺ tumors

Objectives GRP receptor (GRPR) targeted imaging and therapy of tumors, e.g. breast and prostate cancer, by radiolabeled bombesin analogs is a challenging goal. Recent studies have revealed the superior profile of GRPR-antagonists as compared to agonists. Better targeting of PC-3 xenografts in mice plus fast clearance from the GRPR-rich pancreas and background tissues was observed. Combined with their biosafety and tumor growth inhibition GRPR antagonists are attractive alternatives to agonists. We evaluated 2 new linear bombesin antagonists coupled with the chelator DOTA. The latter allows tagging of radionuclides for both diagnostic and therapeutic applications.

Methods H-(β-Ala)₂-JMV594 and H-(β-Ala)₃-JMV594 were assembled on solid support and coupled to DOTA. The peptides were labelled with ¹¹¹In. In vitro assays using GRPR⁺ PC-3 cells were performed to determine affinity and internalization in comparison to the agonist ¹¹¹In-AMBA. Biodistribution studies with PC-3-xenografted female SCID mice were performed at 4 and 24 h post injection (p.i.) of radiopeptides (10 pmol).

Results Of the 2 compounds, DOTA-(β-Ala)₂-JMV594 appeared to be the most promising. Receptor affinity was high (IC₅₀ 1.3 nM), whereas the internalization rate was low, characteristic for antagonists. Biodistribution results revealed very high uptake of radioactivity in the GRPR⁺ PC-3 tumor (17.0±2.8%ID/g - block 1.3±0.3%ID/g) versus the pancreas (3.1 ±1.3%ID/g - block 0.8±0.2%ID/g) at 4 h p.i. and 5.2±0.5%ID/g vs. 1.0±0.2%ID/g in PC-3 and pancreas at 24 h p.i., resulting in a tumor/pancreas ratio > 5. Retention of radioactivity in the kidneys was low, 3.5±0.5%ID/g and 1.9±0.3%ID/g at 4 and 24 h p.i., respectively. ¹¹¹In-DOTA-(β-Ala)₃-JMV594 revealed less promising in vivo data.

Conclusions Based on favourable in vitro and in vivo characteristics, we conclude that DOTA-(β-Ala)₂-JMV594 is a most promising GRPR antagonist for future use in clinical studies