Abstract
Background and Purpose: 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 [18F]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 d4 and -d8
deuterated isotopologues of [18F]JHU94620.
Experimental Approach:
[18F]JHU94620-d8 was
further evaluated to characterize its binding properties, metabolic
stability, formation of BBB-penetrant radiometabolites and
biodistribution in mice and rats. Key Results: The deuterated
[18F]JHU94620 isotopologues showed improved
metabolic stability avoiding the accumulation of BBB-penetrating
radiometabolites in the brain over time. CB2R-specific binding with
KD values in the low nanomolar range was
determined across species. Dynamic PET studies revealed a CB2R-specific
and reversible uptake of
[18F]JHU94620-d8 in the
spleen and to a local hCB2R(D80N) protein overexpression in the
striatal region in rats. Conclusion and Implications: These results
support further investigations of
[18F]JHU94620-d8 in
pathological models and tissues with a CB2R overexpression as a
prerequisite for clinical translation.