This study will test the use of a radioactive substance called [11C]dLop for measuring P-glycoprotein (P-gp) using positron emission tomography (PET) imaging. The P-gp protein acts as a pump' in cells, affecting a variety of functions, such as limiting drug absorption and elimination and decreasing drug penetration into certain tissues, such as the brain. It is a major obstacle to successful chemotherapy because it can pump cancer drugs out of the cells, interfering with treatment. Decreased P-gp function may contribute to disorders such as Parkinson's disease and Alzheimer's disease, whereas higher levels of the protein have been found in patients with epilepsy and in several forms of drug-resistant cancer tumors. This study will determine uptake and clearance of [11C]dLop and the radiation exposure to organs of the body to assess its possible use in further studies of P-gp function.

Healthy normal volunteers between 18 and 65 years of age may be eligible for this study. Candidates are screened with a medical history, physical examination and blood and urine tests.

Participants undergo the following procedures:

• Electrocardiogram (ECG): A test of the electrical function of the heart.
• Brain PET scans: PET imaging uses small amounts of a radioactive chemical called a tracer that labels' active areas of the brain so the activity can be seen with a special camera. The tracer used in this study is [18F]FMPEP-d(2). Before starting the scan, a catheter (plastic tube) is placed in a vein in the arm to inject the tracer and another catheter is placed in an artery in the wrist to obtain blood samples during the scan. For the procedure, the subject lies on the scanner bed. A special mask is fitted to the head and attached to the bed to help keep the person's head still during the scan so the images will be clear. A brief scan is done just before the tracer is injected to provide measures of the brain that are helpful in calculating information from subsequent scans. After the tracer is injected, pictures are taken for about 2.5 hours, while the subject lies still on the scanner bed. Blood and urine tests are done after 24 hours after the scan.
• Magnetic resonance imaging (MRI): An MRI scan is done within 1 year (before or after) of the PET scan. This procedure uses a magnetic field and radio waves to produce images of the brain. The subject lies on a table that is moved into the scanner (a tube-like device), wearing earplugs to muffle the noise o...

P-glycoprotein (P-gp) is an ATP-binding cassette (ABC) transporter and is the major efflux pump in the blood-brain barrier. P-gp has several physiological roles such as limiting drug absorption, active drug elimination, and limits drug penetration into sensitive tissues (e.g., brain and testis) (Fromm, 2004). Reduced activity or expression of P-gp may contribute to neurodegenerative disorders such as Parkinson's and Alzheimer's disease. The reduced activity of P-gp (i.e., decreased neuroprotection at the blood brain barrier) may allow harmful pesticides access to the brain which can damage the brain's dopaminergic cell groups possibly leading to Parkinson's disease (Betarbet et al., 2000; Kortekaas et al., 2005). The increased deposition of beta-amyloid in Alzheimer's disease, may be due in part, to the decreased elimination of cerebral beta-amyloid in brain (Vogelgesang et al., 2002). Conversely, an overexpression of P-gp has been found in epilepsy and in several forms of multi drug resistant cancer tumors (Brandt et al., 2006; Szakacs et al., 2006). In vivo evaluation of P-gp function in the brain and throughout the body is important in disease states, and in therapeutic and diagnostic drug evaluation.

P-gp function has been assessed in healthy volunteers with positron emission tomography (PET) using [11C]verapamil, nevertheless, accurate quantification of this PET radioligand is difficult due to the large contribution of radiometabolites and low signal (Ikoma et al., 2006; Lee et al., 2006; Lubberink et al., 2007). Therefore, we have recently developed [11C]dLop as an alternative radioligand for imaging P-gp function, which will allow a more accurate quantification of P-gp with a higher signal and less contribution of radiometabolites. In the current protocol, we wish to evaluate [11C]dLop in healthy volunteers to determine the kinetics of brain imaging of P-gp function. In order to simulate P-gp dysfunction in healthy volunteers we will administer the P-gp inhibitor tariquidar. We will perform brain and whole body PET scans using [11C]dLop before and after P-gp blockade in order to quantify P-gp function at the blood-brain barrier and determine the peripheral effects of P-gp inhibition in various organs of the body.

• Awouters F, Niemegeers CJ, Janssen PA. Pharmacology of antidiarrheal drugs. Annu Rev Pharmacol Toxicol. 1983;23:279-301. Review. No abstract available.
• Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci. 2000 Dec;3(12):1301-6.
• Bigott HM, Prior JL, Piwnica-Worms DR, Welch MJ. Imaging multidrug resistance P-glycoprotein transport function using microPET with technetium-94m-sestamibi. Mol Imaging. 2005 Jan-Mar;4(1):30-9.

• INCLUSION CRITERIA:

All subjects must be healthy and aged 18-50 years.

EXCLUSION CRITERIA:

• Current psychiatric disease, substance abuse or severe systemic disease based on history and physical exam.
• Laboratory tests with clinically significant abnormalities.
• Prior participation in other research protocols or clinical care in the last year such that radiation exposure including that from this protocol would exceed the guidelines set by the Radiation Safety Committee (RSC).
• Pregnancy or breast feeding.
• Positive HIV test.
• Positive result on urine screen for illicit drugs.
• You cannot lie on your back for extended periods of time.
• Use of blood-thinning medications, current or prior history of coagulopathy.
• Subjects taking medications other than birth control pills.
• Subjects weighing more than 275 pounds.