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 (18)F-Norfallypride, the substituted benzamide tosylate (S)-N-[(1-BOC-2-pyrolidinyl)methyl]-2,3-dimethoxy-5-(3'-tosyloxypropyl)-benzamide) was radiolabeled with (18)F using Kryptofix and K2CO3 in acetonitrile and deprotected with trifluoroacetic acid to yield (S)-(18)F-Norfallypride in approx. 10% radiochemical yields. Norfallypride exhibited an IC50 of 0.63μM for displacing (18)F-fallypride in rat brain slices. In vitro rat brain autoradiographic studies revealed weak binding of (18)F-norfallypride to striatal regions. PET imaging in rats showed low brain uptake of (18)F-norfallypride in the rat brain. Ex vivo brain PET analysis displayed binding of (18)F-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. (18)F-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 (18)F-norfallypride in vivo.