Utilizing PET and MALDI Imaging for Discovery of a Targeted Probe for Brain Endocannabinoid α/β-Hydrolase Domain 6 (ABHD6)

Multimodal imaging provides rich biological information, which can be exploited to study drug activity, disease associated phenotypes, and pharmacological responses. Here we show discovery and validation of a new probe targeting the endocannabinoid alpha/beta-hydrolase domain 6 (ABHD6) enzyme by utilizing positron emission tomography (PET) and matrix-assisted laser desorption/ionization (MALDI) imaging. [18F]JZP-MA-11 as the first PET ligand for in vivo imaging of the ABHD6 is reported and specific uptake in ABHD6-rich peripheral tissues and major brain regions was demonstrated using PET. A proof-of-concept study in nonhuman primate confirmed brain uptake. In vivo pharmacological response upon ABHD6 inhibition was observed by MALDI imaging. These synergistic imaging efforts used to identify biological information cannot be obtained by a single imaging modality and hold promise for improving the understanding of ABHD6-mediated endocannabinoid metabolism in peripheral and central nervous system disorders.

Automated summary

Multimodal imaging, through PET and MALDI imaging, is used to discover and validate a new probe targeting the ABHD6 enzyme. The PET ligand [18F]JZP-MA-11 is reported to have specific uptake in ABHD6-rich tissues and major brain regions, with brain uptake confirmed in a nonhuman primate study. In vivo pharmacological response upon ABHD6 inhibition is observed using MALDI imaging. These synergistic imaging efforts hold promise for improving our understanding of ABHD6-mediated endocannabinoid metabolism in peripheral and central nervous system disorders.