(18F)FCWAY and the Blood-Brain Barrier

Objective: We use the radioligand \[(11)C\]dLop (N-desmethyl-loperamide) in positron emission tomography (PET) studies to measure function of P-gp, an efflux transporter at the blood-brain barrier. Because \[(11)C\]dLop is an avid substrate for P-gp, we see almost no radioactivity in brain at baseline in healthy volunteers. However, we do see increased radioactivity in brain in some patients with dementia, or when we co-administer a medication which blocks the function of P-gp. While \[(11)C\]dLop is useful for detecting increased radioactivity in brain, a disadvantage of \[(11)C\]dLop is that it is not useful for detecting decreased radioactivity in brain. The reason for this is that we have a floor effect, where we are unable to detect less radioactivity than zero. Preclinical studies indicate that increases in P-gp activity (which would manifest as decreased radioactivity in brain) correlate with drug-resistant epilepsy and HIV. To better understand diseases associated with not only increased but also decreased P-gp activity, we wish to identify a radioligand which is a moderate substrate of P-gp. We suspect that \[(18)F\]FCWAY is a moderate substrate for P-gp, because some radioligand gets into brain at baseline, but more gets into brain after administering a drug (disulfiram) which inhibits P-gp. The objective of this study is to determine whether the serotonin 1A antagonist \[(18)F\]FCWAY is a substrate of P-gp by determining whether the P-gp inhibitor, tariquidar, increases uptake of the radioligand into brain. Study Population: We will study up to 45 healthy adults, ages 18-50. Participants must be free of medications, with the exception of birth control pills, as medications may confound our data. or iii patients who received a single PET scan as stated under i), will be invited back to have the option of receiving the second PET scan with tariquidar. A maximum of 15 ubjects will receive both scans. Design: Healthy adults will undergo either 1) a single PET scan of the brain with \[(18)F\]FCWAY (at baseline, or during infusion of intravenous tariquidar or 2) two PET scans (both a baseline and a tariquidar scan). Outcome Measures: If \[(18)F\]FCWAY is a substrate of P-gp, pre-treatment with tariquidar will increase its brain uptake of \[(18)F\]FCWAY and delay the time of peak uptake.