Whole-body biodistribution of the cannabinoid type 1 receptor ligand [18F]MK-9470 in the rat

Abstract

The endocannabinoid system participates in many processes in the body, including memory, reward, pain, motor activity, food intake, energy metabolism, and gastrointestinal functions. [¹⁸F]MK-9470 is a positron emission tomography (PET) ligand that binds with high affinity and selectivity to the cannabinoid type 1 receptor. In order to fully characterize ligand behavior, tracer uptake measured using in vivo microPET was compared with results from ex vivo tissue dissection. Twelve male Sprague-Dawley rats were divided into three subgroups and scanned over time periods of 10min, 30min and 90min using PET. Afterwards, a number of the animals' organs were dissected. Uptake of radioactivity was expressed in terms of %ID/ml and %ID/(g tissue). For comparison of in vivo and ex vivo methods, Bland-Altman plots were computed. The highest uptake of [¹⁸F]MK-9470 was found in the liver and small intestine; the brain showed less uptake, while low and unspecific binding was observed in tissue of the heart, lung, kidney and bone. In the brain, normalized uptake of [¹⁸F]MK-9470 was on average 0.25%ID/ml (range: 0.16 to 0.28%ID/ml). Bland-Altman plots revealed the best agreement between methods for the 90min acquisition protocols. High hepatic accumulation and metabolism of [¹⁸F]MK-9470 occur with mainly enteral excretion, which may vary considerably over time - a finding which may be of relevance in metabolite determination in quantitative brain studies. Comparisons between in vivo and ex vivo methods showed that whole-body distribution of [¹⁸F]MK-9470 using positron emission tomography is a preferable alternative to ex vivo biodistribution, and requires a significantly smaller number of animals.

Keywords: Cannabinoid type 1 receptor; MicroPET; Rat; Whole-body biodistribution; [(18)F]MK-9470.