PET imaging of fatty acid amide hydrolase in the brain: synthesis and biological evaluation of an 11C-labelled URB597 analogue

wyffels, Leonie; Muccioli, Giulio G.; Kapanda, Coco N.; Labar, Geoffray; Bruyne, Sander De; Vos, Filip De; Lambert, Didier M.

doi:10.1016/j.nucmedbio.2010.03.009

Cited by 27 publications

(21 citation statements)

References 47 publications

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“…Significant peripheral metabolism and low brain uptake were also observed, and testing the mechanism of inhibition showed 58 was in fact a noncovalent (reversible) inhibitor of FAAH. 168 Another tracer based on the O -arylcarbamate scaffold that has been prepared is [ 11 C] 59 (also known as [ 11 C]CURB), 169 which is the 11 C-labeled analogue of the known irreversible inhibitor URB694. 167 URB694 was chosen instead of the better studied URB597, since previous work had demonstrated URB694 has better distribution in the brain.…”

Section: Ec 35: Hydrolases Acting On Nonpeptidic Carbon–nitrogen Bonmentioning

confidence: 99%

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

2017

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Hydrolytic enzymes are a large class of biological catalysts that play a vital role in a plethora of critical biochemical processes required to maintain human health. However, the expression and/or activity of these important enzymes can change in many different diseases and therefore represent exciting targets for the development of positron emission tomography (PET) and single-photon emission computed tomography (SPECT) radiotracers. This review focuses on recently reported radiolabeled substrates, reversible inhibitors, and irreversible inhibitors investigated as PET and SPECT tracers for imaging hydrolytic enzymes. By learning from the most successful examples of tracer development for hydrolytic enzymes, it appears that an early focus on careful enzyme kinetics and cell-based studies are key factors for identifying potentially useful new molecular imaging agents.

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Section: Ec 35: Hydrolases Acting On Nonpeptidic Carbon–nitrogen Bonmentioning

confidence: 99%

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

2017

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“…Early reports described the use of 11 C‐radiolabeled analogs of URB597 and URB694 (also known as [ 11 C]‐CURB). [ 11 C]‐CURB showed high‐brain uptake in rodent models with a biodistribution concordant with FAAH expression.…”

Section: Alternative Targets For Positron Emission Tomography Imagingmentioning

confidence: 99%

Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque

Holland

Liang

Rotstein

et al. 2013

Labelled Comp Radiopharmac

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Alzheimer's disease (AD) and related dementias show increasing clinical prevalence, yet our understanding of the etiology and pathobiology of disease-related neurodegeneration remains limited. In this regard, noninvasive imaging with radiotracers for positron emission tomography (PET) presents a unique tool for quantifying spatial and temporal changes in characteristic biological markers of brain disease and for assessing potential drug efficacy. PET radiotracers targeting different protein markers are being developed to address questions pertaining to the molecular and/or genetic heterogeneity of AD and related dementias. For example, radiotracers including [(11) C]-PiB and [(18) F]-AV-45 (Florbetapir) are being used to measure the density of Aβ-plaques in AD patients and to interrogate the biological mechanisms of disease initiation and progression. Our focus is on the development of novel PET imaging agents, targeting proteins beyond Aβ-plaques, which can be used to investigate the broader mechanism of AD pathogenesis. Here, we present the chemical basis of various radiotracers which show promise in preclinical or clinical studies for use in evaluating the phenotypic or biochemical characteristics of AD. Radiotracers for PET imaging neuroinflammation, metal ion association with Aβ-plaques, tau protein, cholinergic and cannabinoid receptors, and enzymes including glycogen-synthase kinase-3β and monoamine oxidase B amongst others, and their connection to AD are highlighted.

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“…As shown in Figure 1, there are continued efforts in the search for suitable FAAH PET tracers, including anadamide analogs, 24 [ 11 C-methyl]URB597 analog, 25 [ 11 C-carbonyl]URB694 ([ 11 C]CURB; 1 ), 26,27 [ 18 F]DOPP ( 2 ), 28,29 [ 11 C]PF-04457845 ( 4 ), 30,31 [ 18 F]PF-9811 ( 5 ), 32 MK-3168 ( 6 ), 30 and most recently [ 11 C]MFTC ( 3 ). 33 To date, only two PET ligands have been reported in human studies, namely [ 11 C]CURB ( 1 ) 34,35 and [ 11 C]MK-3168 ( 6 ).…”

Section: Introductionmentioning

confidence: 99%

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

Wang

Yui²,

Wang

et al. 2015

ACS Chem. Neurosci.

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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.

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PET imaging of fatty acid amide hydrolase in the brain: synthesis and biological evaluation of an 11C-labelled URB597 analogue

Cited by 27 publications

References 47 publications

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque

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

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PET imaging of fatty acid amide hydrolase in the brain: synthesis and biological evaluation of an 11C-labelled URB597 analogue

Cited by 27 publications

References 47 publications

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT

Alternative approaches for PET radiotracer development in Alzheimer's disease: imaging beyond plaque

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

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Product

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