Development and evaluation of deuterated [ 18 F]JHU94620 isotopologues for the non-invasive assessment of the cannabinoid type 2 receptor in brain.

Background: The cannabinoid type 2 receptors (CB2R) represent a target of increasing importance in neuroimaging due to its upregulation under various neuropathological conditions. Previous evaluation of [ ¹⁸ F]JHU94620 for the non-invasive assessment of the CB2R availability by positron emission tomography (PET) revealed favourable binding properties and brain uptake, however rapid metabolism, and generation of brain-penetrating radiometabolites have been its main limitations. To reduce the bias of CB2R quantification by blood-brain barrier (BBB)-penetrating radiometabolites, we aimed to improve the metabolic stability by developing -d ₄ and -d ₈ deuterated isotopologues of [ ¹⁸ F]JHU94620.
Results: The deuterated [ ¹⁸ F]JHU94620 isotopologues showed improved metabolic stability avoiding the accumulation of BBB-penetrating radiometabolites in the brain over time. CB2R-specific binding with K _D values in the low nanomolar range was determined across species. Dynamic PET studies revealed a CB2R-specific and reversible uptake of [ ¹⁸ F]JHU94620-d ₈ in the spleen and to a local hCB2R(D80N) protein overexpression in the striatal region in rats.
Conclusion: These results support further investigations of [ ¹⁸ F]JHU94620-d ₈ in pathological models and tissues with a CB2R overexpression as a prerequisite for clinical translation.
Competing Interests: Declarations. Ethics approval and consent to participate: All studies involving animals were carried out according to the national law on the protection of animals and were approved by the responsible authorities (Landesdirektion Sachsen, No. DD24.1-5131/446/19, TVV 18/18), CD-1 mice and Wistar rats were obtained from the Medizinisch-Experimentelles-Zentrum at Universität Leipzig (Leipzig, Germany) and a pig (German Landrace x German Large White) was obtained from the Lehr- und Versuchsgut Oberholz (Großpösna, Germany). Animals were kept under standard conditions with free access to water and food. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests.
(© 2024. The Author(s).)