Brain and Whole Body Imaging of P-Glycoprotein Function Using [11C]dLop

Condition(s) targeted: P-Glycoprotein; Position Emission Tomography; [11C]dLop; Brain Imaging; Whole Body Imaging

Phase: N/A

Status: Recruiting

Sponsored by: National Institute of Mental Health (NIMH)

Overall contact:
Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

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 ?-amyloid in Alzheimer's disease, may be due in part, to the decreased elimination of cerebral ?-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). Differential sensitivity to inhibition of P-gp localized at the blood-brain barrier, and testis-blood barrier have been shown to be more resistant to inhibition compared to peripheral organs (Choo et al., 2006). Thus, pharmacological inhibition of P-gp function may vary at the blood brain barrier or at other tissue sites, including tumors. 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 and whole body imaging to estimate radiation absorbed doses.

Official title: Brain and Whole Body Imaging of P-Glycoprotein Function Using [11C]dLop

Study design: Prospective

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 ?-amyloid in Alzheimer's disease, may be due in part, to the decreased elimination of cerebral ?-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). Differential sensitivity to inhibition of P-gp localized at the blood-brain barrier, and testis-blood barrier have been shown to be more resistant to inhibition compared to peripheral organs (Choo et al., 2006). Thus, pharmacological inhibition of P-gp function may vary at the blood brain barrier or at other tissue sites, including tumors. 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 and whole body imaging to estimate radiation absorbed doses.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

Criteria:

- INCLUSION CRITERIA:

All subjects must be healthy and aged 18-65 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 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.

Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States; Recruiting

NIH Clinical Center Detailed Web Page

Related publications:

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.

Starting date: January 2008
Last updated: March 18, 2008