4-Borono-2-F-fluoro-L-phenylalanine PET for boron neutron capture therapy-oriented diagnosis: overview of a quarter century of research.

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