[18F]fluoromethylated phenyl-pyrroles and 7-azaindole analog as potential dopamine D4 receptor imaging agents

An association between the dopamine D4 receptor and schizophrenia was recently suggested and the D4 receptor antagonists may thus have potential in elucidating the role of the receptor in schizophrenic patients. The purpose of this study was to develop some of these antagonists as potential dopamine D4 receptor imaging agents for PET. We have prepared 1-(3-[18F]fluoromethylphenyl)-3-([4-(pyridin-2-yl)piperazin-1-yl)methyl) pyrrole (1), 1-(3-[18F]fluoromethylphenyl)-3-([4-(pyridin-2-yl)piperazin-1-yl)methyl) pyrrole (2), and 3-([4-(4-[18F]fluoro methylbenzyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3,-b)pyridine (3) as potential imaging agents for the dopamine D4 receptor for PET. The compounds [18F]1 and [18F]2 were prepared by coupling of (3-[18F]fluoromethylphenyl)-pyrrol-1- yl-3-aldehyde and the piperazine moiety in the presence of NaBH3CN. The [18F]fluorinated aldehyde was obtained in 60-85% yield by the displacement of the corresponding mesylate with F-18-(THF, 90 .deg. C, 5 min). HPLC purification (Alltech Econosil C-18 columm, 250 x 10 mm, 35: 65 = 0.1M NH4CI2H : CH3OH, 4 ml/min, tR=26.6 min) gave the [18F]1 and [18F]2 in 7-12% yield. In the case of azaindole 3, a methlene link was inserted between the piperazinyl and a fluoromethyl phenyl group. Radiochemical synthesis of the [18F]3 was carried out by coupling of the piperazne moiety and [18F]fluoromethylbenzyl mesylate in the presence of NEt3(3:1-CH3CN: DMF, 120 .deg. C, 30 min). Purification was carried out by HPLC using a C-18 column (Alltech Econosil, 50 x 10 mm, 100% 0.1M NH4CO2H for 5 min followed by 40:60=0.1 M NH4CO2H : MeOH, 4 ml/min tR=28.7 min). The time of synthesis including HPLC purification was 100 min. The overall yield of [18F]3 was 10-15% with a radiochemical purity better than 97% and a specific activity greater than 1000 ci/mmol