Synthesis of ¹⁸F-Tetrafluoroborate via radiofluorination of boron trifluoride and evaluation in a murine C6-Glioma tumor model

The sodium/iodide symporter (NIS) is under investigation as a reporter for noninvasive imaging of gene expression. Although ¹⁸F-Tetrafluoroborate (¹⁸F-TFB, ¹⁸F-BF₄-) has shown promise as a PET imaging probe for NIS, the current synthesis method using isotopic exchange gives suboptimal radiochemical yield and specific activity. The aim of this study was to synthesize ¹⁸F-TFB via direct radiofluorination on boron trifluoride (BF₃) to enhance both labeling yield and specific activity and evaluation of specific activity influence on tumor uptake. Methods: An automated synthesis of ¹⁸F-TFB was developed whereby cyclotron-produced ¹⁸F-fluoride was trapped on a quaternary methyl ammonium anion exchange cartridge, then allowed to react with BF₃ freshly preformulated in petroleum ether/tetrahydrofuran (50:1). The resultant ¹⁸F-TFB product was retained on the quaternary methyl ammonium anion exchange cartridge. After the cartridge was rinsed with tetrahydrofuran and water, ¹⁸F-TFB was eluted from the cartridge with isotonic saline, passing through 3 neutral alumina cartridges and a sterilizing filter. Preclinical imaging studies with ¹⁸F-TFB were performed in athymic mice bearing NIS-expressing C6-glioma subcutaneous xenografted tumors to determine the influence of specific activity on tumor uptake. Results: Under optimized conditions, ¹⁸F-TFB was synthesized in a radiochemical yield of 20.0% ± 0.7% (n 5 3, uncorrected for decay) and greater than 98% radiochemical purity in a synthesis time of 10 min. Specific activities of 8.84 ± 0.56 GBq/μmol (n 5 3) were achieved from starting ¹⁸F-fluoride radioactivities of 40-44 GBq. An avid uptake of ¹⁸F-TFB was observed in human NIS (hNIS)-expressing C6-glioma xenografts as well as expected NIS-mediated uptake in the thyroid and stomach. There was a positive correlation between the uptake of ¹⁸F-TFB in hNISexpressing tumor and specific activity. Conclusion: A rapid, practical, and high-specific-Activity synthesis of the NIS reporter probe ¹⁸F-TFB was achieved via direct radiofluorination on BF3 using an automated synthesis system. The synthesis of high-specific-Activity ¹⁸F-TFB should enable future clinical studies with hNIS gene reporter viral constructs.