In vivo biodistribution of no-carrier-added 6-¹⁸F-fluoro-3, 4-dihydroxy-L-phenylalanine (¹⁸F-DOPA), produced by a new nucleophilic substitution approach, compared with carrier-added ¹⁸F-DOPA, prepared by conventional electrophilic substitution

A novel synthetic approach to 6-¹⁸F-fluoro-3, 4-dihydroxy-L-phenylalanine (¹⁸F-DOPA), involving the nucleophilic substitution of a diaryliodonium salt precursor with non-carrier-added ¹⁸F-fluoride, yielded a product with a specific activity that was 3 orders of magnitude higher than the product of the conventional synthesis method involving an electrophilic substitution of a trialkylstannane precursor with ¹⁸F2. We performed a direct comparison of high- and lowspecific- activity ¹⁸F-DOPA in a neuroendocrine tumor model to determine whether this difference in specific activity has implications for the biologic behavior and imaging properties of ¹⁸F-DOPA.

Methods: ¹⁸F-DOPA was produced via the novel synthesis method, yielding ¹⁸F-DOPA-H with a high specific activity (35, 050 ± 4, 000 GBq/mmol). This product was compared in several experiments with conventional ¹⁸F-DOPA-L with a low specific activity (11 ± 2 GBq/mmol). In vitro accumulation experiments with the human pancreatic neuroendocrine tumor cell line BON-1 were performed at both 0°C and 37°C and at 37°C in the presence of pharmacologic inhibitors of proteins involved in the uptake mechanism of ¹⁸FDOPA. Small-animal PET experiments were performed in athymic nude mice bearing a BON-1 tumor xenograft.

Results: At 37°C, the uptake of both ¹⁸F-DOPA-H and ¹⁸F-DOPA-L did not differ significantly during a 60-min accumulation experiment in BON-1 cells. At 0°C, the uptake of ¹⁸F-DOPA-L was significantly decreased, whereas the lower temperature did not alter the uptake of ¹⁸FDOPA- H. The pharmacologic inhibitors carbidopa and tetrabenazine also revealed differential effects between the 2 types of ¹⁸FDOPA in the 60-min accumulation experiment. The small-animal PET experiments did not show any significant differences in distribution and metabolism of ¹⁸F-DOPA-H and ¹⁸F-DOPA-L in carbidopapretreated mice.

Conclusion: The advantages of the novel synthesis of ¹⁸F-DOPA, which relies on nucleophilic fluorination of a diaryliodonium salt precursor, lie in the simplicity of the synthesis method, compared with the conventional, electrophilic approach and in the reduced mass of administered, pharmacologically active ¹⁹F-DOPA. ¹⁸F-DOPA-H demonstrated comparable imaging properties in an in vivo model for neuroendocrine tumors, despite the fact that the injected mass of material was 3 orders of magnitude less than ¹⁸F-DOPA-L.