UNLABELLED: (18)F-trans-4-Fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide ((18)F-FCWAY) is a PET radioligand for imaging serotonin 5-hydroxytryptamine-1A receptors in brain. (18)F-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 (18)F-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 (18)F-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 (18)F-FCWAY (with a corresponding decrease of clearance from 14.8 +/- 7.8 L x h(-1) at baseline to 7.9 +/- 2.8 L x h(-1) after drug treatment (P < 0.05). Using compartmental modeling with input of both (18)F-FCWAY and the radiometabolite (18)F-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 (11)C-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 (18)F-FCWAY, increased the plasma concentration of (18)F-FCWAY, increased brain uptake of activity, and resulted in better visualization of 5-HT(1A) receptor in the brain. Disulfiram is a safe and well-tolerated drug that may be useful for other radioligands that undergo defluorination via CYP2E1.
UNLABELLED: (18)F-trans-4-Fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide ((18)F-FCWAY) is a PET radioligand for imaging serotonin 5-hydroxytryptamine-1A receptors in brain. (18)F-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 (18)F-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 (18)F-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 (18)F-FCWAY (with a corresponding decrease of clearance from 14.8 +/- 7.8 L x h(-1) at baseline to 7.9 +/- 2.8 L x h(-1) after drug treatment (P < 0.05). Using compartmental modeling with input of both (18)F-FCWAY and the radiometabolite (18)F-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 (11)C-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 (18)F-FCWAY, increased the plasma concentration of (18)F-FCWAY, increased brain uptake of activity, and resulted in better visualization of 5-HT(1A) receptor in the brain. Disulfiram is a safe and well-tolerated drug that may be useful for other radioligands that undergo defluorination via CYP2E1.
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