RT Journal Article
SR Electronic
T1 Identification of (<em>R</em>)-[<sup>18</sup>F]YH134 for Monoacylglycerol Lipase Neuroimaging and Exploration of Its Use for Central Nervous System and Peripheral Drug Development
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 300
OP 305
DO 10.2967/jnumed.123.266426
VO 65
IS 2
A1 He, Yingfang
A1 Krämer, Stefanie D.
A1 Grether, Uwe
A1 Wittwer, Matthias B.
A1 Collin, Ludovic
A1 Kuhn, Bernd
A1 Topp, Andreas
A1 Heer, Dominik
A1 O’Hara, Fionn
A1 Honer, Michael
A1 Pavlovic, Anto
A1 Richter, Hans
A1 Ritter, Martin
A1 Rombach, Didier
A1 Keller, Claudia
A1 Gobbi, Luca
A1 Mu, Linjing
YR 2024
UL http://jnm.snmjournals.org/content/65/2/300.abstract
AB This study aimed to evaluate (R)-[18F]YH134 as a novel PET tracer for imaging monoacylglycerol lipase (MAGL). Considering the ubiquitous expression of MAGL throughout the whole body, the impact of various MAGL inhibitors on (R)-[18F]YH134 brain uptake and its application in brain–periphery crosstalk were explored. Methods: MAGL knockout and wild-type mice were used to evaluate (R)-[18F]YH134 in in vitro autoradiography and PET experiments. To explore the impact of peripheral MAGL occupancy on (R)-[18F]YH134 brain uptake, PET kinetics with an arterial input function were studied in male Wistar rats under baseline and blocking conditions. Results: In in vitro autoradiography, (R)-[18F]YH134 revealed a heterogeneous distribution pattern with high binding to MAGL-rich brain regions in wild-type mouse brain slices, whereas the radioactive signal was negligible in MAGL knockout mouse brain slices. The in vivo brain PET images of (R)-[18F]YH134 in wild-type and MAGL knockout mice demonstrated its high specificity and selectivity in mouse brain. A Logan plot with plasma input function was applied to estimate the distribution volume (VT) of (R)-[18F]YH134. VT was significantly reduced by a brain-penetrant MAGL inhibitor but was unchanged by a peripherally restricted MAGL inhibitor. The MAGL target occupancy in the periphery was estimated using (R)-[18F]YH134 PET imaging data from the brain. Conclusion: (R)-[18F]YH134 is a highly specific and selective PET tracer with favorable kinetic properties for imaging MAGL in rodent brain. Our results showed that blocking of the peripheral target influences brain uptake but not the VT of (R)-[18F]YH134. (R)-[18F]YH134 can be used for estimating the dose of MAGL inhibitor at half-maximal peripheral target occupancy.