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

[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.

[1]  Synthesis and in vivo evaluation of a new PET radioligand for imaging the cannabinoid type-1 (CB1) receptors , 2006, NeuroImage.

[2]  J. Sallés,et al.  Characterization of CB1 cannabinoid receptor immunoreactivity in postmortem human brain homogenates , 2006, Neuroscience.

[3]  Ralph Buchert,et al.  Feasibility of central cannabinoid CB1 receptor imaging with [124I]AM281 PET demonstrated in a schizophrenic patient , 2006, Psychiatry Research: Neuroimaging.

[4]  Arman Rahmim,et al.  11C-JHU75528: a radiotracer for PET imaging of CB1 cannabinoid receptors. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[5]  Lars Farde,et al.  Using positron emission tomography to facilitate CNS drug development. , 2006, Trends in pharmacological sciences.

[6]  O. Valverde,et al.  Involvement of the endocannabinoid system in drug addiction , 2006, Trends in Neurosciences.

[7]  K. Mackie,et al.  Identification functional characterization of brainstem cannabinoid CB2 receptors. , 2022 .

[8]  T. Friede,et al.  Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis , 2005, Neurology.

[9]  B. Gorzalka,et al.  Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression? , 2005, Behavioural pharmacology.

[10]  H. Donald Burns,et al.  Screening Cascade and Development of Potential Positron Emission Tomography Radiotracers for mGluR5: In vitro and In vivo Characterization , 2005, Molecular Imaging and Biology.

[11]  J. Brotchie,et al.  A role for endocannabinoids in the generation of parkinsonism and levodopa‐induced dyskinesia in MPTP‐lesioned non‐human primate models of Parkinson's disease , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  C. Lupica,et al.  Endocannabinoid release from midbrain dopamine neurons: a potential substrate for cannabinoid receptor antagonist treatment of addiction , 2005, Neuropharmacology.

[13]  V. Marzo,et al.  Endocannabinoid control of food intake and energy balance , 2005, Nature Neuroscience.

[14]  Ralitza Gueorguieva,et al.  Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction , 2005, Biological Psychiatry.

[15]  M. L. de Ceballos,et al.  Prevention of Alzheimer's Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation , 2005, The Journal of Neuroscience.

[16]  J. Honegger,et al.  Binding affinity and agonist activity of putative endogenous cannabinoids at the human neocortical CB1 receptor. , 2005, Biochemical pharmacology.

[17]  Nathalie Ginovart,et al.  Imaging the Dopamine System with In Vivo [11C]raclopride Displacement Studies: Understanding the True Mechanism , 2005, Molecular Imaging and Biology.

[18]  J. Hoenicka,et al.  Depression in Parkinson's disease is related to a genetic polymorphism of the cannabinoid receptor gene (CNR1) , 2005, The Pharmacogenomics Journal.

[19]  Steven Laureys,et al.  Posterior cingulate, precuneal and retrosplenial cortices: cytology and components of the neural network correlates of consciousness. , 2005, Progress in brain research.

[20]  R. Birch,et al.  Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial , 2004, Pain.

[21]  L Teare,et al.  Cannabis for dyskinesia in Parkinson disease , 2004, Neurology.

[22]  R. Buchert,et al.  [123I]AM281 single-photon emission computed tomography imaging of central cannabinoid CB1 receptors before and after Δ9-tetrahydrocannabinol therapy and whole-body scanning for assessment of radiation dose in tourette patients , 2004, Biological Psychiatry.

[23]  R. Pertwee,et al.  Cannabinoids and glaucoma , 2004, British Journal of Ophthalmology.

[24]  Á. Pazos,et al.  Influence of age, postmortem delay and freezing storage period on cannabinoid receptor density and functionality in human brain , 2004, Neuropharmacology.

[25]  P. Soubrié,et al.  CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity , 2004, International Journal of Obesity.

[26]  L. Iversen,et al.  Cannabis and the brain. , 2003, Brain : a journal of neurology.

[27]  E. Hostetler,et al.  An in vitro assay for predicting successful imaging radiotracers. , 2003, Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging.

[28]  T. Kirkham,et al.  Observational analysis of feeding induced by Δ9-THC and anandamide , 2002, Physiology & Behavior.

[29]  J. Brotchie,et al.  Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: A pilot study , 2001, Neurology.

[30]  Sharon Anavi-Goffer,et al.  Agonist-Induced Internalization and Trafficking of Cannabinoid CB1 Receptors in Hippocampal Neurons , 2001, The Journal of Neuroscience.

[31]  R. Pertwee,et al.  Cannabinoids control spasticity and tremor in a multiple sclerosis model , 2000, Nature.

[32]  David E. Kuhl,et al.  Kinetic Modeling of N-[11C]Methylpiperidin-4-yl Propionate: Alternatives for Analysis of an Irreversible Positron Emission Tomography Tracer for Measurement of Acetylcholinesterase Activity in Human Brain , 1999, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[33]  K. Mackie,et al.  Internalization and Recycling of the CB1 Cannabinoid Receptor , 1999, Journal of neurochemistry.

[34]  A. Hohmann,et al.  The neurobiology of cannabinoid analgesia. , 1999, Life sciences.

[35]  S. Kapur,et al.  Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. , 1999, The American journal of psychiatry.

[36]  N. Volkow,et al.  Large receptor reserve for cannabinoid actions in the central nervous system. , 1999, The Journal of pharmacology and experimental therapeutics.

[37]  K. Mackie,et al.  Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system , 1998, Neuroscience.

[38]  Payton King,et al.  Imaging the Brain Marijuana Receptor: Development of a Radioligand that Binds to Cannabinoid CB1 Receptors In Vivo , 1998, Journal of neurochemistry.

[39]  R. Faull,et al.  Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain , 1997, Neuroscience.

[40]  R. Pertwee.  Pharmacology of cannabinoid CB1 and CB2 receptors. , 1997, Pharmacology & therapeutics.

[41]  N. Volkow,et al.  123I-labeled AM251: a radioiodinated ligand which binds in vivo to mouse brain cannabinoid CB1 receptors. , 1996, European journal of pharmacology.

[42]  M. Herkenham,et al.  Cannabinoid receptor binding and messenger RNA expression in human brain: An in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains , 1994, Neuroscience.

[43]  J. Vanderhaeghen,et al.  Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons , 1992, Neuroscience Letters.

[44]  M. Herkenham,et al.  Neuronal localization of cannabinoid receptors in the basal ganglia of the rat , 1991, Brain Research.

[45]  M. Herkenham,et al.  Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[46]  M. Herkenham,et al.  Cannabinoid receptor localization in brain. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Elliott M. Ross,et al.  Signal sorting and amplification through G protein-coupled receptors , 1989, Neuron.

[48]  R. Lefkowitz,et al.  A quantitative analysis of beta-adrenergic receptor interactions: resolution of high and low affinity states of the receptor by computer modeling of ligand binding data. , 1980, Molecular pharmacology.