PET 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.

- DESCRIPTION OF STUDY POPULATIONS:

For the dose escalation study using oral tariquidar, we will select healthy adult female
and male volunteers (age 18-51 years old). These healthy volunteers will be medication
free, excluding birth control pills. These subjects will be asked to abstain from any
medications 16 days before and 1 week after participation in the study.

For the AD study, we will select male and female AD patients and age-matched volunteers who
are at least 45 years of age.

INCLUSION CRITERIA:

1. Patients with the diagnosis of probable Alzheimer disease. All patients must meet
capacity criteria to consent to research (see Consent documents and process).

2. Healthy volunteers.

EXCLUSION CRITERIA:

1. Current psychiatric disease, illicit substance use, or severe systemic disease based
on history and physical exam.

2. Laboratory tests with clinically significant abnormalities. Normal organ and marrow
function are defined as: total leukocyte count greater than or equal to 3000 cells/ul,
ANC greater than or equal to 1500 cells/ul, platelet count greater than or equal to
100,000 cells/ul, serum creatinine less than or equal to 2.0 times the upper limit of
normal, and bilirubin less than or equal to 1.5 times the upper limit of normal,
hemoglobin 9.0 g/dL , serum calcium less than or equal to 12.0 mg/dL, AST/ALT less
than or equal to 1.5 times the upper limit of normal, PT less than or equal to 1.5
times the upper limit of normal.

3. 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).

4. Pregnancy or breast feeding.

5. Positive HIV test.

6. Positive result on urine screen for illicit drugs.

7. You cannot lie on your back for extended periods of time.

8. Use of blood-thinning medications (such as warfarin; aspirin is allowed), current or
prior history of coagulopathy. This will be necessary only for subjects who have
arterial catheter placement.

9. History of neurological disease other than Alzheimer disease.

10. For oral tariquidar dose-escalation study: Subjects taking medications other than
birth control pills.

11. For Alzheimer s disease patients and age-matched volunteers: Subjects taking
medications that are known substrates of P-gp that cannot be safely discontinued for
this study.