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

Kiichi Ishiwata

doi:10.1007/s12149-019-01347-8

Abstract

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

Highlights

Boron neutron capture therapy (BNCT) is a radiotherapeutic technique that selectively treats tumor cells with highenergy α particles and recoiling 7Li nuclei via 10B(n,α)7Li produced by the neutron irradiation of 10B-containing compounds located selectively in tumor tissues
18F-FBPA positron emission tomography (PET) has expanded to only limited numbers of PET facilities, mainly because BNCT is performed in a small number of institutes with nuclear reactors as a neutron source for BNCT
In 22 of 98 glioma patients in Finland who received BNCT, from 1999 to 2011, a kinetic model based on 18F-FBPA PET predicted + 11% and + 36% higher total weighted doses delivered to tumor and normal brain, respectively, than previously estimated doses due to the non-constant tumor-to-blood concentration ratios [81]

Summary

Introduction

Boron neutron capture therapy (BNCT) is a radiotherapeutic technique that selectively treats tumor cells with highenergy α particles and recoiling 7Li nuclei via 10B(n,α)7Li produced by the neutron irradiation of 10B-containing compounds located selectively in tumor tissues. In 22 of 98 glioma patients in Finland who received BNCT, from 1999 to 2011, a kinetic model based on 18F-FBPA PET predicted + 11% and + 36% higher total weighted doses delivered to tumor and normal brain, respectively, than previously estimated doses due to the non-constant tumor-to-blood concentration ratios [81]. Nariai et al indicated that in patients with malignant brain tumors the T/B ratio of 18F-FBPA after a bolus injection of 18F-FBPA had a significant linear correlation with the T/B ratio of 10B estimated by 1-h constant infusion of 10B-BPA, as simulated using the Runge–Kutta algorithm [84] This type of quantitative evaluation has not been tried in other malignant tumors; Morita et al recently reported that the T/N ratios of 18F-FBPA in head and neck cancers and malignant melanoma were not significantly changed over 120 min in spite of a slight decrease in 18F-FBPA uptake [85]. The melanomas-to-squamous cell carcinoma uptake ratios of 18F-FBPA increased slightly (1.69, 1.73, and 1.93) with time post-injection (30, 60, and 120 min, respectively)

Concluding remarks

Findings

Compliance with ethical standards