Multi-parameter optimization: Development of a morpholin-3-one derivative with an improved kinetic profile for imaging monoacylglycerol lipase in the brain

Preclinical Evaluation of the Reversible Monoacylglycerol Lipase PET Tracer (R)‐[11C]YH132: Application in Drug Development and Neurodegenerative Diseases

“…For the ongoing MAGL project, we have synthesized and investigated [ 11 C]RO7284390 based on Roche's morpholin-3-one derivatives library and [ 18 F]YH149 based on the pyrrolidin-2-one lead structure from the literature. [16,27,28] During the collaboration, we recognized that a good drug candidate may not necessarily lead to a suitable candidate for PET imaging. The pursued features of comparatively slow pharmacokinetics and long target occupancy for a drug candidate are not favorable for a PET tracer due to the inability or lengthy time it takes to reach an equilibrium stage in a practical PET study, as exemplified with [ 11 C]RO7279991 and [ 11 C]RO7284390.…”

Strategies for designing novel positron emission tomography (PET) radiotracers to cross the blood–brain barrier

“…The groups of Liang and Mu subsequently developed reversibly binding MAGL tracers with improved brain uptake and kinetics ([ 18 F]MAGL‐2102, [ 18 F]MAGL‐1902, [ 18 F]YH149, [ 11 C]RO7279991, [ 11 C]PAD, and [ 18 F]MAGL‐4‐11; Figure 7). 119–124 Scaffold selection from the compound libraries are often initially guided by potency measured by the half‐maximal inhibitory concentration (IC 50 ), and followed by selectivity, reversibility, metabolic stability, or rate constant data. Candidates were then evaluated in vitro to assess important parameters, such as P‐gp efflux ratios, off‐target binding, selectivity, and plasma stability.…”

“…Structures of selected MAGL PET tracers 119–124 . Abbreviations: MAGL, monoacylglycerol lipase; PET, positron emission tomography.…”

“…18 F]MAGL-2102, [18 F]MAGL-1902, [ 18 F]YH149, [ 11 C]RO7279991, [ 11 C] PAD, and [18F]MAGL-4-11; Figure7) [119][120][121][122][123][124]. Scaffold selection from the compound libraries are often initially guided by potency measured by the half-maximal inhibitory concentration (IC 50 ), and followed by selectivity, reversibility, metabolic stability, or rate constant data.…”

“…Fortunately, pre-treatment with the P-gp inhibitor elacridar enabled [ 11 C]SCIO-469 to pass the BBB with peak brain uptake of 1.2 SUV, indicating that the radiotracer is a substrate for rodent efflux transporters (Figure8(B)). A subsequent MDCK-MDR1 assay suggested that SCIO-469 is also likely to be a substrate F I G U R E 7 Structures of selected MAGL PET tracers [119][120][121][122][123][124]. Abbreviations: MAGL, monoacylglycerol lipase; PET, positron emission tomography.…”