Evaluation of Pharmacokinetics of 4-borono-2-(18)F-fluoro-L-phenylalanine for Boron Neutron Capture Therapy in a Glioma-bearing Rat Model with Hyperosmolar Blood-brain Barrier Disruption

Unlabelled: This study evaluated the pharmacokinetics and biodistribution of 4-borono-2-(18)F-fluoro-l-phenylalanine ((18)F-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 (18)F-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 (18)F-FBPA and BPA and with or without mannitol-induced hyperosmotic BBB-D. The boron concentration and (18)F radioactivity in tissues were determined by invasive (inductively coupled plasma mass spectroscopy, gamma-counting) and noninvasive PET methods.

Results: The biodistributions of (18)F-FBPA and BPA in F98 glioma-bearing rats were similar after intracarotid administration with BBB-D. The accumulation of BPA and (18)F-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 mug/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), k(12), k(21), and V(1) for intracarotid injection of (18)F-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 k(12)/k(21) 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.