Recent Development of Radiofluorination of Boron Agents for Boron Neutron Capture Therapy of Tumor: Creation of 18F-Labeled C-F and B-F Linkages

Abstract

Boron neutron capture therapy (BNCT) is a binary therapeutic technique employing a boron agent to be delivered to the tumor site followed by the irradiation of neutrons. Biofunctional molecules/nanoparticles labeled with F-18 can provide an initial pharmacokinetic profile of patients to guide the subsequent treatment planning procedure of BNCT. Borono phenylalanine (BPA), recognized by the l-type amino acid transporter, can cross the blood-brain barrier and be accumulated in gliomas. The radiofluoro BNCT agents are reviewed by considering (1) less cytotoxicity, (2) diagnosing and therapeutic purposes, (3) aqueous solubility and extraction route, as well as (4), the trifluoroborate effect. A trifluoroborate-containing amino acid such as fluoroboronotyrosine (FBY) represents an example with both functionalities of imaging and therapeutics. Comparing with the insignificant cytotoxicity of clinical BPA with IC50 > 500 μM, FBY also shows minute toxicity with IC50 > 500 μM. [18F]FBY is a potential diagnostic agent for its tumor to normal accumulation (T/N) ratio, which ranges from 2.3 to 24.5 from positron emission tomography, whereas the T/N ratio of FBPA is greater than 2.5. Additionally, in serving as a BNCT therapeutic agent, the boron concentration of FBY accumulated in gliomas remains uncertain. The solubility of 3-BPA is better than that of BPA, as evidenced by the cerebral dose of 3.4%ID/g vs. 2.2%ID/g, respectively. While the extraction route of d-BPA differs from that of BPA, an impressive T/N ratio of 6.9 vs. 1.5 is noted. [18F]FBPA, the most common clinical boron agent, facilitates the application of BPA in clinical BNCT. In addition to [18F]FBY, [18F] trifluoroborated nucleoside analog obtained through 1,3-dipolar cycloaddition shows marked tumoral uptake of 1.5%ID/g. Other examples using electrophilic and nucleophilic fluorination on the boron compounds are also reviewed, including diboronopinacolone phenylalanine and nonsteroidal anti-inflammatory agents.

Optimizing Boron Neutron Capture Therapy (BNCT) to Treat Cancer: An Updated Review on the Latest Developments on Boron Compounds and Strategies

“…Deng and Yu [ 149 ] put together a summary of the recent development of radiofluorination of boron agents for BNCT. A trifluoroborate-containing amino acid such as fluoroborontyrosine (FBY) could be a potential candidate for BNCT that has both functionalities of imaging and therapeutics.…”

Amino Acid-Based Boron Carriers in Boron Neutron Capture Therapy (BNCT)

“…The biodistribution results for U-87 MG, LN-229, U-118 MG, U-251 MG, FaDu, and A-253 were also confirmed in an in vivo xenograft model using [ 18 F] 9 and [ 14 C]BPA ( Table S5 , entries 2–5; Table S6 , entries 2–4, respectively) [ 68 ]. For a recent review on radiofluorination, see the excellent review article by Deng and Yu [ 69 ].…”

“…S5, entries 2-5; Table S6, entries 2-4, respectively) [68]. For a recent review on radiofluorination, see the excellent review article by Deng and Yu [69].…”

Next generation of boron neutron capture therapy (BNCT) agents for cancer treatment

“…Nevertheless, the two drugs show inherent disadvantages such as relatively low bio‐selectivity of tumor to blood and sparing water solubility of pristine BPA. Although conjugating with fructose may improve water solubility of BPA, 20 due to significant amount of BPA‐fructose complex is used in clinic, and that is harmful to patient. According to the results of pharmacological studies, it is suggested that BPA may be selectively delivered to malignant cells by l ‐type amino acid transporters (LAT), such as LAT1 and ATB 0,+ (amino acid transporter B 0,+ ) 9,21 .…”