Dataset Information

Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase.

ABSTRACT: We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain.

SUBMITTER: Liu P

PROVIDER: S-EPMC4027136 | biostudies-other | 2013 Jun

REPOSITORIES: biostudies-other

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Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase.

Liu Ping P Hamill Terence G TG Chioda Marc M Chobanian Harry H Fung Selena S Guo Yan Y Chang Linda L Bakshi Raman R Hong Qingmei Q Dellureficio James J Lin Linus S LS Abbadie Catherine C Alexander Jessica J Jin Hong H Mandala Suzanne S Shiao Lin-Lin LL Li Wenping W Sanabria Sandra S Williams David D Zeng Zhizhen Z Hajdu Richard R Jochnowitz Nina N Rosenbach Mark M Karanam Bindhu B Madeira Maria M Salituro Gino G Powell Joyce J Xu Ling L Terebetski Jenna L JL Leone Joseph F JF Miller Patricia P Cook Jacquelynn J Holahan Marie M Joshi Aniket A O'Malley Stacey S Purcell Mona M Posavec Diane D Chen Tsing-Bau TB Riffel Kerry K Williams Mangay M Hargreaves Richard R Sullivan Kathleen A KA Nargund Ravi P RP DeVita Robert J RJ

ACS medicinal chemistry letters 20130420 6

We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [(11)C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus ...[more]

PMID: 24900701

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Project description:BackgroundThe brain's endocannabinoid system, the primary target of cannabis, has been implicated in psychosis. The endocannabinoid anandamide is elevated in cerebrospinal fluid of patients with schizophrenia. Fatty acid amide hydrolase (FAAH) controls brain anandamide levels; however, it is unknown if FAAH is altered in vivo in psychosis or related to positive psychotic symptoms.MethodsTwenty-seven patients with schizophrenia spectrum disorders and 36 healthy control subjects completed high-resolution positron emission tomography scans with the novel FAAH radioligand [11C]CURB and structural magnetic resonance imaging. Data were analyzed using the validated irreversible 2-tissue compartment model with a metabolite-corrected arterial input function.ResultsFAAH did not differ significantly between patients with psychotic disorders and healthy control subjects (F1,62.85 = 0.48, p = .49). In contrast, lower FAAH predicted greater positive psychotic symptom severity, with the strongest effect observed for the positive symptom dimension, which includes suspiciousness, delusions, unusual thought content, and hallucinations (F1,26.69 = 12.42, p = .002; Cohen's f = 0.42, large effect). Shorter duration of illness (F1,26.95 = 13.78, p = .001; Cohen's f = 0.39, medium to large effect) and duration of untreated psychosis predicted lower FAAH (F1,26.95 = 6.03, p = .021, Cohen's f = 0.27, medium effect). These results were not explained by past cannabis exposure or current intake of antipsychotic medications. FAAH exhibited marked differences across brain regions (F7,112.62 = 175.85, p < 1 × 10-56; Cohen's f > 1). Overall, FAAH was higher in female subjects than in male subjects (F1,62.84 = 10.05, p = .002; Cohen's f = 0.37).ConclusionsThis first study of brain FAAH in psychosis indicates that FAAH may represent a biomarker of disease state of potential utility for clinical studies targeting psychotic symptoms or as a novel target for interventions to treat psychotic symptoms.

Dataset Information

Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase.

Publications

Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase.

Similar Datasets

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