18F-desmethoxyfallypride: a fluorine-18 labeled radiotracer with properties similar to carbon-11 raclopride for PET imaging studies of dopamine D2 receptors.
We have developed (S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-18F-fluoropropyl)-2- methoxybenzamide (18F-desmethoxyfallypride) as a fluorine-18 radiotracer with properties analogous to that of 11C-raclopride. In vitro experiments in rat brain homogenates showed an association rate constant of 2.16 x 10(8) M(-1)min(-1) and a dissociation rate constant of 0.073 min(-1). High striatal uptake (up to 0.08% injected dose/cc) of 18F-desmethoxyfallypride in rhesus monkeys was observed in PET experiments. The radiotracer cleared from the striata with a dissociation rate of 1.80 x 10(-2) min(-1). Striatum to cerebellum ratios peaked at 3.0 in 30 min after which they decreased steadily. Intravenously administered haloperidol displaced specifically bound 18F-desmethoxyfallypride with a koff of 0.058 min(-1). Synaptic dopamine released by the treatment of the monkeys with d-amphetamine increased the dissociation rate of 18F-desmethoxyfallypride to 0.83 min(-1) thus reducing specifically bound 18F-desmethoxyfallypride by 56% over a period of 42 mins compared to a reduction of only 20% in controls during this time period. The sensitivity of 18F-desmethoxyfallypride towards competition with dopamine should make this radiotracer useful in PET studies to evaluate in vivo pharmacological effects of various agents that alter levels of endogenous dopamine.
Mukherjee
J
J
Franklin McLean Institute, Department of Radiology, University of Chicago, Il 60637, USA. jogm@fciad3.bsd.uchicago.edu
Yang
Z Y
ZY
Brown
T
T
Roemer
J
J
Cooper
M
M
D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D003913:Dextroamphetamine / Q000494:pharmacology; D018492:Dopamine Antagonists; D005462:Fluorine Radioisotopes; D006220:Haloperidol / Q000494:pharmacology; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D012457:Salicylamides / Q000378:metabolism*; D014055:Tomography, Emission-Computed / Q000379:methods*
D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D005462:Fluorine Radioisotopes; D012457:Salicylamides; C100958:desmethoxyfallypride; D020891:Raclopride; D006220:Haloperidol; D003913:Dextroamphetamine