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

Abstract

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. F...

Boron Chemistry for Medical Applications

“…The 4-borono-2-18 F-fluorophenylalanine ( 18 F-BPA) is one of the examples of a dual modality BNCT agent, which is a radiolabeled derivative of BPA as shown in Figure 3 The 18 F-BPA uptake for head and neck cancers can be correlated with the uptake of 18 F-fluorodeoxyglucose [66]. The 18 F-BPA administration has also been reported for numerous types of tumors such as malignant melanomas, malignant gliomas and various head and neck cancers with tumor/normal tissue ratios ranging from 1.5 to 7.8 [67,68].…”

Microdistribution and quantification of the boron neutron capture therapy drug BPA in primary cell cultures of human glioblastoma tumour by NanoSIMS

“…14- 18 LAThas been shown to be over-expressed in malignant tumours [19][20][21] and contributes to the specific uptake of BPA in cancer cells. 22 Pre-accumulation of L-tyrosine can lead to the stimulation of exchange and transport between L-tyrosine intracellularly and L-BPA extracellularly. However, a review of the relevant literature shows that L-amino acid pretreatment is not universally successful in increasing the uptake of L-BPA.…”

Carborane‐Containing Matrix Metalloprotease (MMP) Ligands as Candidates for Boron Neutron‐Capture Therapy (BNCT)

“…[25] For example, 4-10 B-borono-2-18 F-fluoro-l-phenylalanine ( 18 F-FBPA) was developed for monitoring the pharmacokinetics of 4-10 B-boronol-phenylalanine ( 10 B-BPA) used in BNCT with positron emission tomography (PET). [26] For these reasons we have selected to pursue analogs that contain the trifluoromethoxy ether linkage, in addition to the fact that these analogs were among the most potent and selective among the �-sulfone hydroxamates that were previously described. [23,24]…”

“…The trifluoromethoxyphenyl ether moiety in SC‐78080 and SC‐77964 contains fluorine ( 19 F) atoms that will enable the use of magnetic resonance spectroscopy for the detection and localization of fluorinated drugs in tumors, which is essential to demonstrating the localization of drug in target tissues . For example, 4‐ 10 B‐borono‐2‐ 18 F‐fluoro‐l‐phenylalanine ( 18 F‐FBPA) was developed for monitoring the pharmacokinetics of 4‐ 10 B‐boronol‐phenylalanine ( 10 B‐BPA) used in BNCT with positron emission tomography (PET) . For these reasons we have selected to pursue analogs that contain the trifluoromethoxy ether linkage, in addition to the fact that these analogs were among the most potent and selective among the ɑ‐sulfone hydroxamates that were previously described …”