The role of radiolabeling in BNCT tracers for enhanced dosimetry and treatment planning

Abstract

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are potent technologies for non-invasive imaging of pharmacological and biochemical processes in both preclinical and advanced clinical research settings. In the field of radiation therapy, boron neutron capture therapy (BNCT) stands out because it harnesses biological mechanisms to precisely target tumor cells while preserving the neighboring healthy tissues. To achieve the most favorable therapeutic outcomes, the delivery of boron-enriched tracers to tumors must be selective and efficient, with a substantial concentration of boron atoms meticulously arranged in and around the tumor cells. Although several BNCT tracers have been developed to facilitate the targeted and efficient delivery of boron to tumors, only a few have been labeled with PET or SPECT radionuclides. Such radiolabeling enables comprehensive in vivo examination, encompassing crucial aspects such as pharmacodynamics, pharmacokinetics, tumor selectivity, and accumulation and retention of the tracer within the tumor. This review provides a comprehensive summary of the essential aspects of BNCT tracers, focusing on their radiolabeling with PET or SPECT radioisotopes. This leads to more effective and targeted treatment approaches which ultimately enhance the quality of patient care with respect to cancer treatment.

Keywords: BNCT; PET; SPECT; radiolabeling; theranostics, targeted therapy.

Figure 1

Schematic overview of the BNCT principle and its impact on tumor cell improvement.

Figure 2

A schematic overview of various imaging modalities, highlighting their unique capabilities, strengths, and limitations. PET and SPECT exhibit several promising advantages over traditional imaging technologies.

Figure 3

Schematic illustration of radiolabeling strategies for molecular imaging. (A) Direct radiolabeling of BNCT tracers. (B) Indirect radiolabeling of BNCT tracers.

Figure 4

Introducing the pioneering and highly effective BNCT tracers. (A) Structure of L-BPA and corresponding PET tracers. (B) Structure of O-carborane and corresponding PET tracer. (C) Structure of D-BPA and corresponding PET tracer.

Scheme 1

Synthesis of¹⁸F labeled ¹⁸F-FBPA analogues. (A) Electrophilic substitution reaction for the radiofluorination of (L)-4-dihydroxy-borophenylalanine using ¹⁸[F]-F₂ or ¹⁸F-acetylhypofluorite (¹⁸F-AcOF). (B) Synthesis of ¹⁸F-FBPA-fructose complex utilizing fructose at neutral pH: Enhancing water solubility for superior biocompatibility.

Scheme 2

Synthesis of ¹⁸F-Labeled BPA analogue (¹⁸F-FBPA) through nucleophilic radio-fluorination reaction with diborono precursor for enhanced molecular imaging capabilities.

Figure 5

The structural diversity and half-lives of alkyl- and acyltrifluoroborates: Unlocking the promising potential for BNCT applications.

Figure 6

Synthesis and preclinical evaluation of organotrifluoroborates (A) Detailed radiosynthesis of ¹⁸F labeled fluoroboronotyrosine ¹⁸F-FBY.(B)B16-F10 tumor bearing mouse was injected with ¹⁸F-FBY, and a PET image was acquired 1 hr postinjection. ¹⁸F-FBY exhibited high tumor accumulation compared to that of the healthy tissues. The biodistribution study (n = 4), which was conducted 1 hr postinjection utilizing B16-F10 tumor-bearing mice, further supports the PET imaging data. Adapted with permission from , copyright 2019, American Chemical Society. (C, D) Representative organotrifluoroborates sugar conjugate.

Figure 7

Schematic representation of ⁶⁴Cu labeled BNCT tracers. (A) ⁶⁴Cu labeled BSH-n(R)-DOTA precursor (n= 0, 2, 3; R= Arg). (B) Schematic illustration of synthesis of ⁶⁴Cu-labeled boronated porphyrins nanoparticles.

Figure 8

⁶⁴Cu labeled DSPE-BCOP-5T and preclinical evaluation. (A) Schematic illustration of the synthesis of DSPE-BCOP-5T BNCT tracer. (B) PET/CT images have been obtained for ⁶⁴Cu-DSPE-BCOP-5T at 30 min, 24, and 36 hr postinjection using 4T1 tumor-bearing mice. High tumor uptake is indicated by white arrows (n = 3). (C) Biodistribution data was acquired for ⁶⁴Cu-DSPE-COP-5T in 4T1 tumor-bearing mice 24 hr postinjection (mean ± SE, %ID/g) (n = 6). Adapted with permission from , copyright 2020, American Chemical Society.

Figure 9

⁶⁴Cu-NOTA-boronsome synthesis, uptake and preclinical evaluation. (A) Schematic illustration of boronated liposome loaded with chemotherapeutic drug (B) CT and PET/CT images of 4T1 tumor bearing mice using ⁶⁴Cu-NOTA-boronsome, (C) Average tumor volume (mm³) (n = 9) of each group of mice utilizing various treatment process calculated up to 20 days post treatment, ****p < 0.001. Adapted with permission from , copyright 2022, Springer Nature Limited.

Figure 10

Schematic illustration of immune drug-loaded B-COF particles and preclinical studies. (A) Schematic representation of the synthesis of carborane-derived covalent organic framework (B˗COF) by the condensation of 1, 3, 5-tris (4-aminophenyl)-benzene (TAPB) and p-carborane-1, 10-phenyl-dialdehyde (B˗CHO) under an optimized condition. (B) PET/CT images of B16F10 tumor-bearing mice at an indicated time point after intratumoral injection of ⁸⁹Zr˗Boroncapsule (n=3). (C, D) Average tumor volume (mm³) (n = 6) of each group of mice utilizing various treatment processes calculated up to 40 days post treatment, ****p < 0.0001 with, (C) B16F10, and (D) MC38 xenograft. Adapted with permission from , copyright 2022, Springer Nature Limited.

Figure 11

Representative boron-installed radiolabeled PSMA and cyclic RGD agents. (A) Schematic illustration of selected boron installed PSMA agents 1a, 1d, and 1f. (B) Schematic illustration of boron-installed cyclic RGD peptide⁶⁷Ga-B-cRGD and ¹²⁵I-B-cRGD. Adapted with permission from , copyright 2022, American Chemical Society.

Figure 12

Representative images of ¹²³I-61-B-AuNPs and preclinical studies. (A) Schematic illustration of gold nanoparticles functionalized with boron cages (B-AuNPs). (B) B-AuNPs conjugated to anti-HER2 antibody (61IgG) to form 61-B-AuNPs and radiolabeled with ¹²³I to yield¹²³I-61-B-AuNPs. (C) SPECT/CT images of N87 xenograft-bearing mice intravenously injected with¹²³I-B-AuNPs or ¹²³I-61-B-AuNPs at 12 and 36 hr postinjection. (D) Correlation between the tumor-to-muscle ration obtained from biodistribution studies using gamma counter and that derived from boron content determined by ICPMS (R² = 0.8519, p < 0.05). Adapted with permission from , copyright 2019, Elsevier B.V.