Improving radiopeptide pharmacokinetics by adjusting experimental conditions for bombesin receptor-targeted imaging of prostate cancer

: Aim: Prostate cancer (PC) is a major health problem. The Gastrin Releasing Peptide Receptor (GRPR) offers a promising target for staging and monitoring of PC since it is overexpressed in PC and not in normal prostatic tissue. To improve GRPR-mediated imaging we investigated the impact of various experimental conditions on pharmacokinetics using the 111In-labelled bombesin (BN) analogue DOTA-AMBA that binds to the GRPR with high affinity. Besides the frequently used PC-3 cell line, the androgen sensitive VCaP celline was used as human PC xenografts in nude mice. Methods: Non-purified [111In]DOTA-AMBA was compared with HPLC-purified [111In]DOTA-AMBA. Effect of specific activity was studied administrating a constant amount of activity (0.1 MBq) [111In]DOTA-AMBA supplemented with different amounts of DOTA-AMBA (1-3000 pmol). GRPR was saturated with Tyr4-Bombesin, 1 and 4h prior to injection of [111In]DOTA-AMBA. Results: GRPR-positive tumor tissue showed a significant 2 to 3-fold increase in absolute uptake after HPLC-purification while a stable tumor-to-pancreas ratio remained. Low peptide amounts (10 pmoles) resulted in a decline in uptake of 43% in tumor, 49% in kidney and 92% in pancreas. Tumor-to-pancreas ratio improved six-fold from 0.1±0 at 10 pmol up to 0.6±0.2 at 3000 pmol (P<0.01). GRPR saturation 4h prior to injection of [111In]DOTA-AMBA resulted in improvement of the tumor-to-pancreas ratio from 0.10±0.3 to 0.22±0.2 (P<0.01) and tumor-to-kidney ratio increased from 0.92±0.16 up to 3.45±0.5 (P<0.01). Conclusion: Besides specific peptide characteristics also the experimental conditions, such as HPLC-purification, variations in peptide mass and GRPR saturation prior to [111In]DOTA-AMBA administration affect radiopeptide pharmacokinetics. Experimental conditions therefore need to be carefully selected in order to compose standardised protocols for optimal targeting.