Imaging of CB1 Receptors Using (11C)SD5024

Overview

Background: \- The cannabinoid type 1 (CB1) receptor is a protein found on some brain cells. It may play a role in obesity or some psychiatric disorders such as schizophrenia. Imaging studies like positron emission tomography (PET) can show where CB1 receptors are located. A new radioactive chemical, 11C-SD5024, may be able to show these receptors more clearly than previous radioactive chemicals. Better images of CB1 receptors in the brain may help improve our understanding of obesity and psychiatric disorders. This information may lead to better treatments. Objectives: \- To test how well a new radioactive chemical, 11C-SD5024, is taken up by the brain during imaging studies. Eligibility: \- Healthy volunteers between 18 and 50 years of age who are able to have positron emission tomography scans. Design: * All participants will be screened with a physical exam, medical history, and blood tests. * Participants will be in one of three groups for the study. Each group will receive 11C-SD5024 and have a different set of imaging studies. * Group 1 will have a magnetic resonance imaging (MRI) scan and PET scan of the brain. They will also have blood and urine tests. * Group 2 will have a whole-body PET scan, as well as blood and urine tests. * Group 3 will have an MRI scan of the brain, followed by two PET scans of the brain. They will also have blood and urine tests. The two PET scans can happen on the same day or on two different days.

The cannabinoid type 1 (CB(1)) receptor is one of the most abundant G protein-coupled receptors in the brain (Matsuda et al 1990). It is found on glutamatergic, dopaminergic, and gamma aminobutyric acid (GABA)-ergic synaptic terminals and mediates the effects of endocannabinoids (ECs), which suppresses the release of neurotransmitters. The CB(1) receptor is a target for drug therapy, including the use of a CB(1) receptor antagonist as an appetite suppressant. Our laboratory recently developed a promising positron emission tomography (PET) ligand for the CB(1) receptor: \[(11)C\]SD5024 (Donohue et al 2008a). Previous studies from our laboratory used two PET ligands to image CB(1) receptors (11)C-MePPEP and (18)F-FMPEP-d(2) (Yasuno et al 2008; Donohue et al 2008b) and found that the latter provides more accurate and precise measurement. We also found that clearance of (11)C-MePPEP from brain was too slow for (11)C-labeling (Terry et al 2010). Although we are currently using \[(18)F\]FMPEP-d(2) , the major disadvantage of the current radioligand is that it washes out slowly from the brain, and accurate quantitation requires relatively fast washout. If \[(11)C\]SD5024 is amenable to quantitation in human subjects, then it may prove to be a useful ligand for studying potential pathophysiological changes of this receptor. The purpose of this protocol is (1) to perform brain imaging using \[(11)C\]SD5024 in healthy volunteers to characterize brain uptake and distribution; (2) to perform whole body PET studies in healthy volunteers in order to estimate radiation absorbed doses for \[(11)C\]SD5024; and (3) to perform brain test-retest studies in healthy volunteers to further examine how precise measurements of receptor binding are, and to determine optimal parameters for future experiments using \[(11)C\]SD5024. Successful development of a PET radioligand to image CB1 receptors has the potential to significantly impact our understanding and clinical management of neuropsychiatric (eg, schizophrenia) (Eggan et al 2008) and metabolic (eg, obesity) (Gazzerro et al 2007) disorders. Future experiments would include studies of relevant neuropsychiatric disorders.