Imaging of CB1 Receptors Using (11C)SD5024

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.

- INCLUSION CRITERIA:

Healthy control subjects aged 18 50 whose medical history, physical exam, electrocardiogram
(ECG), and laboratory test results are within normal limits within one year of the PET scan
will be eligible to participate.

EXCLUSION CRITERIA:

Any recent or past history of psychiatric illness or severe systemic disease based on
history and physical exam.

Serious medical illness likely to modify brain anatomy and/or physiology (head trauma, past
brain surgery, neurological disorders such as epilepsy, Parkinson disease, and psychiatric
disorders such as schizophrenia and depression)

Any current substance or alcohol abuse, with the exception of nicotine.

Positive urine toxicology screen

Radiation exposure from participation in other research protocols in the last year such
that the additional radiation exposure from this protocol would exceed annual limits.

Pregnant or breastfeeding.

Claustrophobia (applies to Parts 1 and 3 only).

Metallic (ferromagnetic) implants, including pacemakers or other implanted electrical
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on
the wall of a large artery), metallic prostheses (including metal pins and rods, heart
valves, and cochlear implants), permanent eyeliner, implanted delivery pump, shrapnel
fragments, and possible small metal fragments in the eye (applies to Parts 1 and 3 only).

Unable to lie flat on back for up to 2.5 hours.