4-Borono-2-(18)F-fluoro-l-phenylalanine PET for boron neutron capture therapy-oriented diagnosis: overview of a quarter century of research

4-(10)B-Borono-2-(18)F-fluoro-l-phenylalanine ((18)F-FBPA) was developed for monitoring the pharmacokinetics of 4-(10)B-borono-l-phenylalanine ((10)B-BPA) used in boron neutron capture therapy (BNCT) with positron emission tomography (PET). The tumor-imaging potential of (18)F-FBPA was demonstrated in various animal models. Accumulation of (18)F-FBPA was higher in melanomas than in non-melanoma tumors in animal models and cell cultures. (18)F-FBPA was incorporated into tumors mediated mainly by L-type amino acid transporters in in vitro and in vivo models. Tumoral distribution of (18)F-FBPA was primarily related to the activity of DNA synthesis. (18)F-FBPA is metabolically stable but is incorporated into melanogenesis non-enzymatically. These in vitro and in vivo characteristics of (18)F-FBPA corresponded well to those of (10)B-BPA. Nuclear magnetic resonance and other studies using non-radioactive (19)F-(10/11)B-FBPA also contributed to characterization. The validity and reliability of (18/19)F-FBPA as an in vivo probe of (10)B-BPA were confirmed by comparison of the pharmacokinetics of (18)F-FBPA and (10)B-BPA and direct measurement of both (18)F and (10)B in tumors with various doses of both probes administered by different routes and methods. Clinically, based on the kinetic parameters of dynamic (18)F-FBPA PET, the estimated (10)B-concentrations in tumors with continuous (10)B-BPA infusion were similar to those measured directly in surgical specimens. The significance of (18)F-FBPA PET was verified for the estimation of (10)B-concentration and planning of BNCT. Later (18)F-FBPA PET has been involved in (10)B-BPA BNCT of patients with intractable tumors such as malignant brain tumors, head and neck tumors, and melanoma. Usually a static PET scan is used for screening patients for BNCT, prediction of the distribution and accumulation of (10)B-BPA, and evaluation of treatment after BNCT. In some clinical trials, a tumor-to-normal tissue ratio of (18)F-FBPA > 2.5 was an inclusion criterion for BNCT. Apart from BNCT, (18)F-FBPA was demonstrated to be a useful PET probe for tumor diagnosis in nuclear medicine: better tumor-to-normal brain contrast compared with (11)C-methionine, differentiation of recurrent and radiation necrosis after radiotherapy, and melanoma-preferential uptake. Further progress in (18)F-FBPA studies is expected for more elaborate evaluation of (10)B-concentrations in tumors and normal tissues for successful (10)B-BPA BNCT and for radiosynthesis of (18)F-FBPA to enable higher (18)F-activity amounts and higher molar activities.