Development of PET tracers for investigation of arginase-related pathways

As arginase is a potential biomarker of disease and a novel therapeutic target, it was hypothesized that arginase inhibitors could be used as reference scaffolds for the development of molecular imaging probes. Using an optimized Cu-mediated 18F-fluorination strategy, radiolabeled arginase inhibitors were synthesized and evaluated in vivo for the first time. The best candidate ([18F]FBMARS) was obtained with a radiochemical yield of 4% ± 1% and a molar activity up to 72 GBq.µmol-1. Micro PET studies indicated fast blood clearance of the radiotracer (7.3 ± 0.6 min), arginase-mediated uptake, and a tumor accumulation peak nearly 40 minutes after intravenous administration. The successful synthesis of a radiolabeled arginase inhibitor opened new perspectives on the development of a customized molecular imaging "toolbox" to investigate the possibility of using statins to influence arginase/NOS signaling pathways. The synthesis of [18F]atorvastatin was first attempted using the Cu-mediated radiofluorination strategy. However, as atorvastatin was one of the most complex substrates labeled with this 18F-fluorodeboronation strategy to date, the final yields achieved were very modest (2%). The radiosynthesis was then improved (to >20%) via an optimized version of another newly developed late-stage radiofluorination strategy: the Ru-intermediated 18F-deoxyfluorination. PET imaging studies revealed an extensive liver uptake and did not identify any off-target accumulation site beyond hepatic tissue.