Synthesis and Preliminary PET Imaging Studies of a FAAH Radiotracer ([¹¹C]MPPO) Based on α-Ketoheterocyclic Scaffold

Abstract

Fatty acid amide hydrolase (FAAH) is one of the principle enzymes for metabolizing endogenous cannabinoid neurotransmitters such as anandamide, and thus regulates endocannabinoid (eCB) signaling. Selective pharmacological blockade of FAAH has emerged as a potential therapy to discern the endogenous functions of anandamide-mediated eCB pathways in anxiety, pain and addiction. Quantification of FAAH in the living brain by positron emission tomography (PET) would help our understanding of the endocannabinoid system in these conditions. While most FAAH radiotracers operate by an irreversible (‘suicide’) binding mechanism, a FAAH tracer with reversibility would facilitate quantitative analysis. We have identified and radiolabeled a reversible FAAH inhibitor, 7-(2-[11C]methoxyphenyl)-1-(5-(pyridin-2-yl)oxazol-2-yl)heptan-1-one ([11C]MPPO) in 13% radiochemical yield (non-decay corrected) with >99% radiochemical purity and 2 Ci/μmol (74 GBq/μmol) specific activity. The tracer showed moderate brain uptake (0.8 SUV) with heterogeneous brain distribution. However, blocking studies with a potent FAAH inhibitor URB597 demonstrated a low to modest specificity to the target. Measurement of lipophilicity, metabolite and efflux pathway analysis were also performed to study the pharmacokinetic profile of [11C]MPPO. In all, we reported an efficient radiolabeling and preliminary evaluation of the first-in-class FAAH inhibitor [11C]MPPO with α-ketoheterocyclic scaffold.

Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2

“…Based on the results of in vitro autoradiography and in vivo PET studies on rat brain, we speculated that insufficient brain permeability of [ 11 C]­QCA might be induced by ATP-binding cassette efflux transporters located at the blood–brain barrier, ,− particularly, P-glycoprotein (PgP, ABCB1) and breast cancer resistance protein (Bcrp, ABCG2). To test this hypothesis, we carried out PET imaging studies of [ 11 C]­QCA on wild-type and PgP/Bcrp knockout (ABCB1a/1b –/– ABCG2 –/– ) mice and compared pharmacokinetic profiles, particularly brain uptake and clearance.…”

“…As we previously reported, , the PET dynamic images were reconstructed using ASIPro VW software (Analysis Tools and System Setup/Diagnostics Tool, Siemens Medical Solutions). Volumes of interest, including the whole brain, cerebral cortex, cerebellum, striatum, thalamus, and pons were placed using ASIPro software.…”

Synthesis and Preclinical Evaluation of Sulfonamido-based [11C-Carbonyl]-Carbamates and Ureas for Imaging Monoacylglycerol Lipase

“…For pretreatment studies, URB597 (3 mg/kg), SAR127303 (1 mg/kg), JZL184 (3 mg/kg) or KML29 (3 mg/kg) dissolved in 300 µL saline containing 10% ethanol and 5% Tween ® 80 was injected at 30 min via the tail vein catheter before the injection of [ 11 C]SAR127303 ([ 11 C] 5a ) or [ 11 C]TZPU ([ 11 C] 5f ). As we previously reported, 43 the PET dynamic images were reconstructed using ASIPro VW software (Analysis Tools and System Setup/Diagnostics Tool, Siemens Medical Solutions). Volumes of interest, including the whole brain, cerebral cortex, cerebellum, striatum, thalamus and pons were placed using ASIPro software.…”

Role of Nuclear Imaging to Understand the Neural Substrates of Brain Disorders in Laboratory Animals: Current Status and Future Prospects

“…Alternative targets to study the ECS by neuroimaging techniques are substrates for enzymes involved in endocannabinoid degradation, transport or synthesis. Two examples are the MAGL ligand [ 11 C]10 (MAGL-0519), which demonstrated high specific binding and selectivity in vitro and in vivo (Cheng et al, 2018) and the radiolabeled reversible FAAH inhibitor [ 11 C]MPPO, which showed moderate uptake with heterogeneous distribution in rodents brain (Wang et al, 2016). Figure 4C depicts the Monte Carlo simulation slice images of the activated thalamus, cerebellum and globus pallidus for the ECS.…”