Automated synthesis of [ 18F]DCFPyL via direct radiofluorination and validation in preclinical prostate cancer models

摘要

Background Prostate-specific membrane antigen (PSMA) is frequently overexpressed and upregulated in prostate cancer. To date, various~(18)F- and~(68)Ga-labeled urea-based radiotracers for PET imaging of PSMA have been developed and entered clinical trials. Here, we describe an automated synthesis of [~(18)F]DCFPyL via direct radiofluorination and validation in preclinical models of prostate cancer. Methods [~(18)F]DCFPyL was synthesized via direct nucleophilic heteroaromatic substitution reaction in a single reactor TRACERlab FX_(FN)automated synthesis unit. Radiopharmacological evaluation of [~(18)F]DCFPyL involved internalization experiments, dynamic PET imaging in LNCaP (PSMA+) and PC3 (PSMA?) tumor-bearing BALB/c nude mice, biodistribution studies, and metabolic profiling. In addition, reversible two-tissue compartmental model analysis was used to quantify pharmacokinetics of [~(18)F]DCFPyL in LNCaP and PC3 tumor models. Results Automated radiosynthesis afforded radiotracer [~(18)F]DCFPyL in decay-corrected radiochemical yields of 23?±?5?% ( n ?=?10) within 55?min, including HPLC purification. Dynamic PET analysis revealed rapid and high uptake of radioactivity (SUV_(5min)0.95) in LNCaP tumors which increased over time (SUV_(60min)1.1). Radioactivity uptake in LNCaP tumors was blocked in the presence of nonradioactive DCFPyL (SUV_(60min)0.22). The muscle as reference tissue showed rapid and continuous clearance over time (SUV_(60min)0.06). Fast blood clearance of radioactivity resulted in tumor-blood ratios of 1.0 after 10?min and 8.3 after 60?min. PC3 tumors also showed continuous clearance of radioactivity over time (SUV_(60min)0.11). Kinetic analysis of PET data revealed the two-tissue compartmental model as best fit with K _(1)?=?0.12, k _(2)?=?0.18, k _(3)?=?0.08, and k _(4)?=?0.004?min~(?1), confirming molecular trapping of [~(18)F]DCFPyL in PSMA+ LNCaP cells. Conclusions [~(18)F]DCFPyL can be prepared for clinical applications simply and in good radiochemical yields via a direct radiofluorination synthesis route in a single reactor automated synthesis unit. Radiopharmacological evaluation of [~(18)F]DCFPyL confirmed high PSMA-mediated tumor uptake combined with superior clearance parameters. Compartmental model analysis points to a two-step molecular trapping mechanism based on PSMA binding and subsequent internalization leading to retention of radioactivity in PSMA+ LNCaP tumors. Electronic supplementary material The online version of this article (doi:10.1186/s13550-016-0195-6) contains supplementary material, which is available to authorized users.