NIMH DIRP Molecular Imaging Branch - Section on PET Imaging

Figure Legend: We recently developed two PET radioligands—¹¹C-MePPEP and ¹⁸F-FMPEP-d2—for imaging CB1 receptors in human brain. The upper right figure shows distribution of radioactivity in a healthy human brain, consistent with the known widespread distribution of CB1 receptors. Because of the long half-life of fluorine-18, radioactivity in brain and plasma can accurately be measured for up to five hours.

Background: Marijuana acts by stimulating the cannabinoid subtype 1 (CB1) receptor in the brain. This receptor has recently been a target for therapeutic drug development – e.g., drugs that can reduce appetite or suppress the urge to smoke cigarettes. CB1 receptors are found in nearly every organ in the body, and may be involved in several neuropsychiatric and metabolic disorders.

Our laboratory developed two PET radioligands—¹¹C-MePPEP and ¹⁸F-FMPEP-d2—that bind reversibly and with high specific signal in monkey brain. We then used these radioligands to image CB1 receptors in the human brain. ¹¹C-MePPEP and ¹⁸F-FMPEP-d2 yielded an effective dose similar to other PET radioligands labeled with either ¹¹C or ¹⁸F. The high uptake in brain indicates that both of these radioligands can be used to image CB1 receptors in brain and perhaps in the periphery (Terry et al 2009, 2010) (PDF File).

We then extended this work in a study that was the first to demonstrate that cortical CB1 receptor downregulation may be a neuroadaptation that promotes cannabis dependence in human brain (Hirvonen et al 2012b). (PDF File) Using PET imaging, we found reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in human subjects who chronically smoked cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After approximately four weeks of continuously monitored abstinence from cannabis on a secure research unit, CB1 receptor density returned to normal levels. This study was the first direct demonstration of cortical cannabinoid CB1 receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.

In collaboration with the National Institute of Alcohol Abuse and Alcoholism (NIAAA), we scanned patients with alcoholism using a similar experimental design: at baseline and after one month abstinence. In contrast to cannabis abusers who had regionally selective and reversible down regulation of CB1 receptor, patients with alcoholism had a global reduction of CB1 receptors that did not reverse after one month of abstinence (Hirvonen et al., 2012c; (PDF File)

References:
J. Hirvonen, R.S. Goodwin, C.-T. Li, G.E. Terry, S.S. Zoghbi, C. Morse, V.W. Pike, N.D. Volkow, M.A. Huestis, and R.B. Innis. Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in heavy cannabis users. Mol. Psychiatry. 17: 642-649, 2012b. (PDF File)

J. Hirvonen, P. Zanotti Fregonara, J.C. Umhau, D.T. George, D. Rallis-Frutos, C.H. Lyoo, C.-T. Li, C.S. Hines, H. Sun, G. Terry, S.S. Zoghbi, C. Morse, V.W. Pike, R.B. Innis, M. Heilig. Reduced cannabinoid CB1 receptor binding in alcohol dependence measured with positron emissio(PDF File)n tomography. Mol. Psychiatry. In press. 2012c. (PDF File)

G.E. Terry, J. Hirvonen, J-S. Liow, S.S. Zoghbi, R. Gladding, J.T. Tauscher, J.M. Schaus, L. Phebus, C.C. Felder, C.L. Morse, S.R. Donohue, V.W. Pike, C. Halldin, and R.B. Innis.< Imaging and quantitation of cannabinoid CB₁ receptors in human and monkey brains using ¹⁸F-labeled inverse agonist radioligands. J. Nucl. Med., 51: 112-120, 2010. (PDF File)

G. Terry, J.-S. Liow, S.S. Zoghbi, J. Hirvonen, A. Farris, A. Lerner, J. Tauscher, J. Schaus, L. Phebus, C. Felder, C. Morse, J. Hong, V.W. Pike, C. Halldin, and R.B. Innis. Quantitation of cannabinoid CB₁ receptors in healthy human brain using positron emission tomography and an inverse agonist radioligand. NeuroImage, 48: 362-370, 2009. (PDF File)