[18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor

doi:10.1073/pnas.0703472104

[¹⁸F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor

*Imaging Research, Merck Research Laboratories, West Point, PA 19486;
^‡Division of Nuclear Medicine, University Hospital and Katholieke Universiteit Leuven, B-3000 Leuven, Belgium;
^§Laboratory for Radiopharmacy and
^¶Centre for Clinical Pharmacology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium;
^‖Merck Research Laboratories, B-1180 Brussels, Belgium;
^‡‡Metabolic Disorders and
^††Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065; and
**Clinical Pharmacology, Merck Research Laboratories, Upper Gwynedd, PA 19454

Communicated by Michael E. Phelps, University of California School of Medicine, Los Angeles, CA, April 20, 2007 (received for review November 15, 2006)

Abstract

[¹⁸F]MK-9470 is a selective, high-affinity, inverse agonist (human IC₅₀, 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed for use in human brain imaging. Autoradiographic studies in rhesus monkey brain showed that [¹⁸F]MK-9470 binding is aligned with the reported distribution of CB1 receptors with high specific binding in the cerebral cortex, cerebellum, caudate/putamen, globus pallidus, substantia nigra, and hippocampus. Positron emission tomography (PET) imaging studies in rhesus monkeys showed high brain uptake and a distribution pattern generally consistent with that seen in the autoradiographic studies. Uptake was blocked by pretreatment with a potent CB1 inverse agonist, MK-0364. The ratio of total to nonspecific binding in putamen was 4–5:1, indicative of a strong specific signal that was confirmed to be reversible via displacement studies with MK-0364. Baseline PET imaging studies in human research subject demonstrated behavior of [¹⁸F]MK-9470 very similar to that seen in monkeys, with very good test–retest variability (7%). Proof of concept studies in healthy young male human subjects showed that MK-0364, given orally, produced a dose-related reduction in [¹⁸F]MK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, [¹⁸F]MK-9470 has the potential to be a valuable, noninvasive research tool for the in vivo study of CB1R biology and pharmacology in a variety of neuropsychiatric disorders in humans. In addition, it allows demonstration of target engagement and noninvasive dose-occupancy studies to aid in dose selection for clinical trials of CB1R inverse agonists.

inverse agonist occupancy

Footnotes

^†To whom correspondence should be addressed at:
Nuclear Imaging Research, Merck Research Laboratories, WP44D-225, Sumneytown Pike, West Point, PA 19486.
E-mail: donald_burns{at}merck.com
Author contributions: H.D.B., K.V.L., S.S.-B., T.G.H., W.-s.E., R.G., C.R., P.R., S.A.S., J.C., W.K.H., J.P.J., L.S.L., P.L., M.T.G., K.G., J.A.W., T.M.F., and R.J.H. designed research; K.V.L., S.S.-B., T.G.H., G.B., W.-s.E., R.G., C.R., B.C., S.P., S.K., A.V., A.V.H., P.D., I.D.L., W.K.H., J.P.J., L.S.L., P.L., M.T.G., J.d.H., and L.M. performed research; T.G.H. and G.B. contributed new reagents/analytic tools; H.D.B., S.S.-B., G.B., W.-s.E., R.G., B.C., S.P., A.V., P.R., S.A.S., J.C., K.G., T.M.F., and R.J.H. analyzed data; and H.D.B., K.V.L., S.S.-B., T.G.H., G.B., W.-s.E., R.G., C.R., B.C., A.V.H., P.D., I.D.L., S.A.S., K.G., J.A.W., J.d.H., L.M., T.M.F., and R.J.H. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0703472104/DC1.
↵ §§ A report (50) on [¹¹C]MePPEP, another PET tracer for the CB1R, appears promising on the basis of preclinical studies.
Abbreviations:

Δ9-THC,

Δ9-tetrahydrocannabinol;

CB1R,

cannabinoid-1 receptor;

PET,

positron emission tomography;

AUC,

area under the curve;

TAC,

time–activity curve;

SUV,

standardized uptake value.
Freely available online through the PNAS open access option.