PET Imaging of P-glycoprotein Function Using [11C]dLop
Condition: Healthy
Study type: Observational

Summary: 
      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 51 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 of the machine during the scanning
           process. The test takes about 1 hour....
    

Detailed description: 
      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 PET scans using [11C]dLop before and after P-gp blockade in order to
      quantify P-gp function at the blood-brain barrier.
    

Observational model: Case-Crossover
Time perspective: Prospective
Keywords: P-Glycoprotein; Positron Emission Tomography; Blood Brain Barrier; Quantitative Imaging; Multi-Drug Transporter; Healthy Volunteer; HV