Disulfiram Inhibits Defluorination of 18F-FCWAY, Reduces Bone Radioactivity, and Enhances Visualization of Radioligand Binding to Serotonin 5-HT1A Receptors in Human Brain

18F-trans-4-Fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY) is a PET radioligand for imaging serotonin 5-hydroxytryptamine-1A receptors in brain. 18F-FCWAY undergoes significant defluorination, with high uptake of radioactivity in the skull and resulting spillover contamination in the underlying neocortex. The cytochrome P450 enzyme CYP2E1 defluorinates many drugs. We previously showed that miconazole, an inhibitor of CYP2E1, blocks defluorination of FCWAY in rats. Here, we used 18F-FCWAY to test the ability of the less toxic agent disulfiram to inhibit defluorination in humans. Methods: Eight healthy volunteers underwent a PET scan before and after administration of 500 mg of disulfiram (n = 6) or 2,000 mg of cimetidine (n = 2). Seven of the subjects had arterial blood sampling during both scans. Results: Although cimetidine had relatively small and variable effects on 2 subjects, disulfiram reduced skull radioactivity by about 70% and increased peak brain uptake by about 50% (n = 5). Disulfiram decreased plasma-free 18F-fluoride ion (from peak levels of 340% ± 62% standardized uptake value (SUV) to 62% ± 43% SUV; P < 0.01) and increased the concentration of the parent 18F-FCWAY (with a corresponding decrease of clearance from 14.8 ± 7.8 L·h−1 at baseline to 7.9 ± 2.8 L·h−1 after drug treatment (P < 0.05). Using compartmental modeling with input of both 18F-FCWAY and the radiometabolite 18F-FC (trans-4-fluorocyclohexanecarboxylic acid), distribution volumes attributed to the parent radioligand unexpectedly decreased about 40%–60% after disulfiram, but the accuracy of the radiometabolite correction is uncertain. Disulfiram changed the shape of the brain time–activity curves in a manner that could occur with inhibition of the efflux transporter P-glycoprotein (P-gp). However, disulfiram showed no in vivo efficacy in monkeys to enhance the uptake of the known P-gp substrate 11C-loperamide, suggesting that the effects of disulfiram in humans were mediated entirely by inhibition of CYP2E1. Conclusion: A single oral dose of disulfiram inhibited about 70% of the defluorination of 18F-FCWAY, increased the plasma concentration of 18F-FCWAY, increased brain uptake of activity, and resulted in better visualization of 5-HT1A receptor in the brain. Disulfiram is a safe and well-tolerated drug that may be useful for other radioligands that undergo defluorination via CYP2E1.