Synthesis and biological evaluation of 18F-Norfallypride in the rodent brain using PET imaging

Norfallypride (N-[(2-pyrolidinyl)methyl]-2,3-dimethoxy-5-(3’-fluoropropyl)benzamide), an analog of fallypride, has been synthesized and evaluated as a potential PET imaging agent for dopamine receptors with increased subtype selectivity. In order to synthesize 18F-Norfallypride, the substituted benzamide tosylate (S)-N-[(1-BOC-2-pyrolidinyl)methyl]-2,3-dimethoxy-5-(3’-tosyloxypropyl)-benzamide) was radiolabeled with 18F using Kryptofix and K2CO3 in acetonitrile and deprotected with trifluoroacetic acid to yield (S)-18F-Norfallypride in approx. 10% radiochemical yields. Norfallypride exhibited an IC50 of 0.63 μM for displacing 18F-fallypride in rat brain slices. In vitro rat brain autoradiographic studies revealed weak binding of 18F-norfallypride to striatal regions. PET imaging in rats showed low brain uptake of 18F-norfallypride in the rat brain. Ex vivo brain PET analysis displayed binding of 18F-norfallypride in several brain regions. With respect to the cerebellum, ex vivo PET ratios were: striatum > 3; hypothalamus > 2; hippocampus ~ 2; cerebellar nuclei > 2 while autoradiographic ratios were 14, 9, 4 and 6 respectively. 18F-Norfallypride exhibited a unique binding profile to rat brain regions known to contain significant amounts of dopamine D3 and serotonin 5HT3 receptors. Efforts are currently under way to increase brain permeability and fully characterize the binding of 18F-norfallypride in vivo.