2- and 4-[18F]fluorotropapride, two specific D2 receptor ligands for positron emission tomography: N.C.A. syntheses...

Tropapride, (exo)-2,3-dimethoxy-N-[8-(phenylmethyl)-8- azabicyclo[3.2.1]oct-3-yl]benzamide hydrochloride, has been labeled with fluorine-18 at the 2- and 4-positions of its benzylic group. Two synthetic pathways were investigated: the first one required the alkylation of the norbenzyl precursor with 2- or 4-[18F]fluorobenzyl bromide (radiochemical yield of 5% EOB, 180 min); the second method consisted of a reductive amination of norbenzyl tropapride with 2- or 4-[18F]fluorobenzaldehyde (20% EOB, 110 min). In both cases, the specific activity was found to be greater than 1 Ci/mumol (EOS). Animal studies in rats showed the percentage of the injected dose localizing in the whole brain to be 0.6 +/- 0.09 and 0.2 +/- 0.03 at 2 h post injection for the para- and the ortho-[18F]fluoro analogs of tropapride respectively. Cerebral biodistribution studies showed at 4 h a striatum uptake of 5 +/- 0.7% of the injected dose per gram of striatum for the para derivative with a low fixation into the frontal cortex and the cerebellum (% ID/g FC < 0.4 and % ID/g Cb < 0.3). The selectivity of 4-[18F]fluorotropapride for D2 dopaminergic sites was demonstrated through blocking experiments with ketanserin, spiperone and halopemide. The saturability was confirmed by the use of variable specific activities. These preliminary results showed that 4-[18F]fluorotropapride can be considered as a potent radiopharmaceutical for the study of the dopaminergic system with PET.