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Evaluation of Pharmacokinetics of 4-Borono-2-¹⁸F-Fluoro-L-Phenylalanine for Boron Neutron Capture Therapy in a Glioma-Bearing Rat Model with Hyperosmolar Blood–Brain Barrier Disruption

¹ Institute of Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
² Department of Pharmacy, Taipei Veterans General Hospital, Taipei, Taiwan
³ Institute of Radiological Sciences, Central Taiwan University of Science and Technology, Taichung, Taiwan
⁴ Deprtment of Medicine, National Yang-Ming University, Taipei, Taiwan
⁵ Department of Engineering and System Science, National Tsing Hua University, Hsinchu, Taiwan

This study evaluated the pharmacokinetics and biodistribution of 4-borono-2-¹⁸F-fluoro-L-phenylalanine (¹⁸F-FBPA) after intracarotid injection and with blood–brain barrier disruption (BBB-D) in F98 glioma-bearing F344 rats. The pharmacokinetics of L-p-boronophenylalanine (BPA) and ¹⁸F-FBPA following different administration routes were compared to demonstrate the optimal delivery route and the time period for thermal neutron irradiation. Methods: F98 glioma-bearing rats were injected intravenously or intracarotidly with ¹⁸F-FBPA and BPA and with or without mannitol-induced hyperosmotic BBB-D. The boron concentration and ¹⁸F radioactivity in tissues were determined by invasive (inductively coupled plasma mass spectroscopy, -counting) and noninvasive PET methods. Results: The biodistributions of ¹⁸F-FBPA and BPA in F98 glioma-bearing rats were similar after intracarotid administration with BBB-D. The accumulation of BPA and ¹⁸F-FBPA in brain tumor and the tumor-to-ipsilateral brain ratios were the highest after intracarotid injection with BBB-D, whereas the retention of boron drugs in contralateral brains exhibited only nonsignificant differences compared with those after intracarotid injection without BBB-D and intravenous injection. The high boron concentration in brain tumor (76.6 µg/g) and the high tumor-to-ipsilateral brain ratio (6.3) may afford enough radiation doses to destroy the tumor cells while sparing the normal tissues in boron neutron capture therapy. The pharmacokinetic parameters of k_el, k₁₂, k₂₁, and V₁ for intracarotid injection of ¹⁸F-FBPA with BBB-D derived from the open 2-compartment model are 0.0206 ± 0.0018 min^–1, 0.0260 ± 0.0016 min^–1, 0.0039 ± 0.0003 min^–1, and 3.1 ± 0.1 mL, respectively. The effect of BBB-D varied depending on the anesthetic agents used and the anesthetic conditions. A smaller degree of BBB-D and, thus, lower boron concentrations in tumor and ipsilateral brain were observed under isoflurane anesthesia than under ketamine anesthesia. The k₁₂/k₂₁ ratio may serve as a good indication for evaluating the extent of BBB-D, tumor uptake, and tumor-to-brain ratio after intracarotid injection of boron compounds. Conclusion: Our findings provide important information for establishing an optimal treatment protocol when intracarotid injection with BPA after BBB-D is applied in clinical boron neutron capture therapy.

Key Words: boron neutron capture therapy • 4-borono-2-¹⁸F-fluoro-L-phenylalanine • F98 glioma • blood–brain barrier disruption • PET

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JNM 2005 46: 7a-8a. [Full Text]