The proposed work builds on our previous extensive neuroimaging studies studies of alcohol and alcohol abuse using positron emission tomography (PET) and high-field magnetic resonance spectroscopic imaging. The objective of this proposal is to set the stage for hypothesis-driven human neuroimaging studies with PET and ethanol labeled with carbon- 11.
The first aim i nvolves the regioselective synthesis of [t 1C]ethanol labeled on either the methyl group carbon atom (11CH3CH2OH) or the hydroxymethyl group carbon atom (CH311CH2OH), and also bearing deuterium instead of ordinary hydrogen on the same carbon atom as the hydroxy group (11CH3CD2OH and CH311CD2OH). These strategies are both hypothesized to slow the rate of appearance of carbon-11 metabolites of ethanol, compared to that of the previously described CH3 llCH2OH, and so improve the radiopharmaceutical properties of [11C]ethanol. Measurement of deuterium isotope effects may also allow us to probe aspects of the metabolism of ethanol in tomographically isolated human organs, in living subjects.
The second aim i s the development of a rapid purification method capable of producing radiopharmaceutical grade [11C] ethanol for intravenous administration to human subjects.
The third aim i s to characterize the proposed radiotracers in baboon PET experiments so that permission for human studies can be sought. This will involve evaluation of brain and plasma kinetics, and also radiation dosimetric studies in abdominal organs.
The fourth aim i s to conduct conventional biodistribution and metabolism studies in rodents to complement the baboon studies, A final aim is the synthesis of [11C]acetaldehyde (11CH3CHO ' CH311CHO, l tCH3CDO and CH311CDO) corresponding to the initial catabolites of the four forms of [11C]ethanol to be made, and preliminary rodent and PET studies with these tracers.
| Li, Zizhong; Xu, Youwen; Warner, Don et al. (2012) Alcohol ADME in primates studied with positron emission tomography. PLoS One 7:e46676 |
| Gifford, Andrew N; Espaillat, Mel Pilar; Gatley, S John (2008) Biodistribution of radiolabeled ethanol in rodents. Drug Metab Dispos 36:1853-8 |
| Glaser, Sherrye T; Gatley, S John; Gifford, Andrew N (2006) Ex vivo imaging of fatty acid amide hydrolase activity and its inhibition in the mouse brain. J Pharmacol Exp Ther 316:1088-97 |
| Gatley, S John; Volkow, Nora D; Wang, Gene-Jack et al. (2005) PET imaging in clinical drug abuse research. Curr Pharm Des 11:3203-19 |
