Brain and Whole Body Imaging of P-Glycoprotein Function Using [11C]dLop
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.
Time Perspective: Prospective
To measure P-glycoprotein function in healthy volunteers by performing brain PET imaging studies with [11C]dLop.
William C Kreisl, M.D.
National Institute of Mental Health (NIMH)
United States: Federal Government
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