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

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