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Whole-Body Biodistribution and Radiation Dosimetry of the Human Cannabinoid Type-1 Receptor Ligand ¹⁸F-MK-9470 in Healthy Subjects

¹ Division of Nuclear Medicine, University Hospital and K.U.Leuven, Leuven, Belgium; ² Imaging, Merck Research Laboratories, West Point, Pennsylvania; ³ Clinical Pharmacology, Merck Research Laboratories, West Point, Pennsylvania; ⁴ Clinical Pharmacology Europe, Merck Research Laboratories, Brussels, Belgium; and ⁵ Laboratory of Radiopharmacy, K.U.Leuven, Leuven, Belgium

Correspondence: For correspondence or reprints contact: Koen Van Laere, MD, PhD, DSc, Division of Nuclear Medicine, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium. E-mail: koen.vanlaere{at}uzleuven.be

The cannabinoid type-1 (CB1) receptor is one of the most abundant G-coupled protein receptors in the human body and is responsible for signal transduction of both endogenous and exogenous cannabinoids. The endocannabinoid system is strongly implicated in regulation of homeostasis and several neuropsychiatric disorders, obesity, and associated comorbidities, such as dyslipidemia and metabolic syndrome. We have used whole-body PET/CT to characterize the biodistribution and dosimetry of a novel high-affinity, subtype-selective radioligand, ¹⁸F-MK-9470, in healthy male and female subjects. Methods: Eight nonobese subjects (5 men, 3 women; age, 22–54 y) underwent serial whole-body PET/CT for 6 h after a bolus injection of 251 ± 25 MBq ¹⁸F-MK-9470 (N-[2-(3-cyano-phenyl)-3-(4-(2-¹⁸F-fluorethoxy)phenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylproponamide). Source organs were delineated 3-dimensionally using the combined morphologic and functional data. Residence times were derived from time–activity profiles using both the trapezoid rule and curve fitting. Individual organ doses and effective doses were determined using the OLINDA software package, with different approaches for gastrointestinal and urinary excretion modeling. Results: ¹⁸F-MK-9470 is taken up slowly in the brain, reaching a plateau at approximately 90–120 min after bolus injection and is excreted predominantly through the hepatobiliary system. The gallbladder, upper large intestine, small intestine, and liver are the organs with the highest absorbed dose (average: 159, 98, 87, and 86 µGy/MBq, respectively). The mean effective dose (ED) was 22.8 ± 4.3 µSv/MBq, indicating relatively low intersubject variability and a mean value in the range of many commercially available ¹⁸F-labeled radiopharmaceuticals. Brain uptake was relatively high compared with that of existing central nervous system ligands for other receptors, between 3.2% and 4.9% of the injected dose. Conclusion: The estimated radiation burden of ¹⁸F-MK-9470 for PET CB1 receptor imaging shows relatively low variability between subjects and has an acceptable ED, which allows multiple serial cerebral scans of good image quality, while remaining within the risk category class II-b defined by the World Health Organization and the International Commission for Radiation Protection for a standard injected activity (185–370 MBq).

Key Words: cannabinoid type-1 receptor • ¹⁸F-MK-9470 • PET • dosimetry • biodistribution • healthy subjects

COPYRIGHT © 2008 by the Society of Nuclear Medicine, Inc.

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