Preclinical Evaluation of 5F-αMe-3BPA for Improving Pharmacokinetics in Boron Neutron Capture Therapy

Background/Objectives: Boron neutron capture therapy (BNCT) relies on the selective delivery of boron-10 to tumor cells. Although 4-[10B]borono-L-phenylalanine (BPA) is currently the only clinically approved BNCT agent, it is limited by poor L-type amino acid transporter 1 (LAT1)/LAT2 selectivity and aqueous solubility. We previously developed 3-borono-5-fluoro-α-methyl-L-phenylalanine (5F-αMe-3BPA), a novel BPA derivative designed to be a LAT1-targeted BNCT/positron emission tomography theranostic agent. This study comprehensively characterizes its pharmacological profile and explores its pharmacokinetic optimization by modulating renal organic anion transporter 1 (OAT1). Methods: Transport kinetics of BPA, related analogs, and 5F-αMe-3BPA were analyzed in HEK293 cells stably expressing LAT1 or LAT2 using Michaelis–Menten analysis. Time-dependent cellular uptake and intracellular retention of BPA and 5F-αMe-3BPA were evaluated in T3M-4 pancreatic cancer cells with or without the LAT1 inhibitor JPH203. In vivo biodistribution was examined in T3M-4 tumor-bearing mice after intravenous administration of 5F-αMe-3BPA or BPA, with assessment of probenecid pretreatment. Results: 5F-αMe-3BPA retained LAT1 affinity comparable to that of BPA while showing markedly reduced LAT2-mediated transport, indicating improved LAT1/LAT2 selectivity. In T3M-4 cells, 5F-αMe-3BPA showed stronger LAT1 dependence, higher steady-state accumulation, and better intracellular retention than BPA under amino acid-containing conditions. Although 5F-αMe-3BPA achieved favorable tumor-to-plasma and tumor-to-muscle ratios in vivo, it was rapidly cleared from circulation. Probenecid pretreatment increased plasma exposure, reduced early renal accumulation, and significantly enhanced tumor boron accumulation, reaching approximately twofold higher levels than control. Conclusions: These findings establish 5F-αMe-3BPA as a highly LAT1-selective BNCT candidate and identify probenecid pretreatment as a clinically translatable pharmacokinetic strategy for maximizing therapeutic boron delivery.