Fluorinated benzamide neuroleptics--III. Development of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2, 3-dimethoxybenzamide as an improved dopamine D-2 receptor tracer.
We have prepared five new analogs (n-propyl, iso-propyl, allyl, n-butyl, and iso-butyl) of the dopamine D-2 receptor antagonist, FPMB which result from modifications of the ethyl group at the pyrrolidine nitrogen in FPMB. As expected, all new derivatives showed higher apparent lipophilicity (log kw), with iso-butyl being the most lipophilic (log kw = 2.52), followed by the allyl derivative (log kw = 2.43). The allyl group showed the largest increase in affinity (from 0.26 nM for the ethyl substituent to 0.03 nM for the allyl substituent, almost 10-fold), followed by the n-propyl substituent which showed approximately five-fold better affinity than did the ethyl substituent. Radiosynthesis of (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2, 3-dimethoxybenzamide ([18F]fallypride) was carried out by nucleophilic substitution reaction of (S)-N-[(1-allyl-2-pyrrolidinyl) methyl]-5-(3-tosyloxypropyl)-2,3-dimethoxybenzamide with no carrier added 18F-. [18F]Fallypride was obtained in approximately 20-40% yields (EOS/EOB, decay corrected) in specific activities of 900-1700 Ci/mmol after reverse phase HPLC purification in 60 min from EOB. High striatal uptake (upto 2.5% injected dose/g) of [18F]fallypride in rats was observed with striatal/cerebellar ratios of 17, 42, 63 and 122 at 30, 60, 90 and 120 min post-injection, respectively. PET experiments with [18F]fallypride in a cebus monkey showed a brain uptake of 0.10% injected dose/cc. In rhesus monkeys [18F]fallypride showed rapid specific uptake in the striata (0.04-0.06% injected dose/cc) with striata/cerebellum ratios of approx. 3.0 at 14 min, 5.0 at 35 min and 8 at 70 min post-injection. Specifically bound [18F]fallypride was displaced with haloperidol (1 mg/kg) with a half-life of 18 min in the rhesus monkey.
Mukherjee
J
J
Franklin McLean Institute, Department of Radiology, University of Chicago, IL 60637, USA.
Yang
Z Y
ZY
Das
M K
MK
Brown
T
T
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D001549:Benzamides / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002428:Cebus; D002851:Chromatography, High Pressure Liquid; D005462:Fluorine Radioisotopes; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D011849:Radioactive Tracers; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D014150:Antipsychotic Agents; D001549:Benzamides; D005462:Fluorine Radioisotopes; C094948:N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide; D011759:Pyrrolidines; D011849:Radioactive Tracers; D017448:Receptors, Dopamine D2