Marked reductions in brain uptake of this radioligand in transgenic mice may be due to reduced cerebral blood flow relative to that in wild-type mice. Specific [11C]6-OH-BTA-1 binding to Abeta plaques, if any, is probably very low, as reflected in the small FR/CE and PA/CE ratio differences. FR/CE and PA/CE ratios are considerably higher in AD patients while Abeta plaque densities in 22-month-old transgenic mice may be expected to show essentially the same density as is observed in the AD brain. This implies that the absence of tracer retention in 22-month-old transgenic mice may be due to the smaller number of Abeta plaque binding sites and/or to lower affinity of the binding sites for [11C]6-OH-BTA-1 as compared with AD patients. [11C]6-OH-BTA-1 shows excellent brain uptake in mice.

( 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 5 6) or 2,000 mg of cimetidine (n 5 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 5). Disulfiram decreased plasma-free 18 F-fluoride ion (from peak levels of 340% 6 62% standardized uptake value (SUV) to 62% 6 43% SUV; P , 0.01) and increased the concentration of the parent 18 F-FCWAY (with a corresponding decrease of clearance from 14.8 6 7.8 LÁh 21 at baseline to 7.9 6 2.8 LÁh 21 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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This study evaluated 18 F-labeled IMPY [6-iodo-2-(4′-N,N-dimethylamino)phenylimidazo[1,2-a]pyridine] derivatives as agents for imaging β-amyloid plaque with positron emission tomography (PET). The precursor for radiolabeling and reference compounds was synthesized in up to five steps from commercially accessible starting materials. One of the two N-methyl groups of IMPY was substituted with either a 3-fluoropropyl (FPM-IMPY) or a 2-fluoroethyl (FEM-IMPY) group. FPM-IMPY and FEM-IMPY were found to have moderate affinity for Aβ-aggregates with K i = 27 ± 8 and 40 ± 5 nM, respectively. A "one-pot" method for 18 F-2-fluoroethylation and 18 F-3-fluoropropylation of the precursor was developed. The overall decaycorrected radiochemical yields were 26-51%. In PET experiments with normal mouse, high uptake of activity was obtained in the brain after iv injection of each probe: 6.4% ID/g for