PET Imaging of Cannabinoid CB1 Receptors Using [18F]FMPEP-d2

BRAIN IMAGING Objective The central cannabinoid receptor (CB1) is one of the most abundant neuromodulatory receptors in the brain. It is found on glutamatergic, dopaminergic and GABA-ergic synaptic terminals and belongs to G-protein coupled receptor family. The CB1 is a target for drug therapy, including the use of an antagonist as an appetite suppressant. The central cannabinoid receptor CB1 has never been visualized in humans. In collaboration with Eli Lilly, we developed a promising PET ligand for the CB1 receptor: \[18F\]FMPEP-d2 ((3R,5R)-5-(3-(fluoromethoxy)phenyl)-3-((R)-1-phenylethylamino)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-2-one). Study Population In the current protocol, we wish to evaluate \[18F\]FMPEP-d2 in approximately 10 healthy subjects. Design Brain imaging studies will consist of subject evaluation followed by PET and MRI scans. Outcome Measures We intend to determine the kinetics of brain uptake and washout, clearance in the plasma, and the distribution volume of \[18F\]FMPEP-d2 calculated with compartmental modeling. Distribution volume is proportional to the density of receptors and is equal to the ratio at equilibrium of uptake in brain to the concentration of parent radiotracer in plasma. WHOLE BODY DOSIMETRY Objective Should the brain imaging studies prove to be successful, we will continue with whole body dosimetry studies. Preliminary dosimetry studies with \[18F\]d2-FMPEP have been performed in nonhuman primates; however, these need to be continued in humans before further investigation of this novel tracer can continue. Study Population In the current protocol, we wish to evaluate \[18F\]FMPEP-d2 in approximately 10 additional healthy subjects. Design The whole body dosimetry studies will consist of subject evaluation followed by a PET scan. Outcome Measures We intend to determine the whole body distribution of activity and thereby calculate radiation exposure to organs of the body. BRAIN IMAGING WITH TEST/RE-TEST Objective Should the brain imaging and dosimetry studies prove to be successful, we will continue with test/retest brain imaging studies. Test/retest studies with \[18F\]FMPEP-d2 will provide evidence of reproducibility and strengthen the assurance that this radioligand can be used to assess pathology. Previous investigations in developing a CB1 receptor PET tracer have demonstrated the need to test reproducibility (Terry, In Writing; Burns et al 2007). Study Population In the current protocol, we wish to evaluate \[18F\]FMPEP-d2 in approximately 10 additional healthy subjects. Design The brain imaging test/retest studies will consist of subject evaluation followed by one MRI and two PET scans. Outcome Measures We intend to determine the reproducibility of the outcome measures from the brain imaging, namely, distribution volume.