Synthesis and Preliminary PET Imaging Studies of a FAAH Radiotracer ([¹¹C]MPPO) Based on α-Ketoheterocyclic Scaffold.
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-[(11)C]methoxyphenyl)-1-(5-(pyridin-2-yl)oxazol-2-yl)heptan-1-one ([(11)C]MPPO) in 13% radiochemical yield (nondecay 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 [(11)C]MPPO. In all, we reported an efficient radiolabeling and preliminary evaluation of the first-in-class FAAH inhibitor [(11)C]MPPO with α-ketoheterocyclic scaffold.
Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.
Lu
L
Wang
Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.
Joji
J
Yui
Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.
Qifan
Q
Wang
Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.
Yiding
Y
Zhang
Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.
Wakana
W
Mori
Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.
Yoko
Y
Shimoda
Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.
Masayuki
M
Fujinaga
Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.
Katsushi
K
Kumata
Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.
Tomoteru
T
Yamasaki
Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.
Akiko
A
Hatori
Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.
Benjamin H
BH
Rotstein
Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.|Advion BioSystems, 10 Brown Road, Suite 101, Ithaca, New York 14850, United States.
Thomas Lee
TL
Collier
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Charlestown, Massachusetts 02129, United States.
Chongzhao
C
Ran
Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.
Neil
N
Vasdev
Molecular Imaging Center, National Institute of Radiological Sciences , Chiba 263-8555, Japan.
Ming-Rong
MR
Zhang
Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School , Boston, Massachusetts 02114, United States.
Steven H
SH
Liang
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000581:Amidohydrolases / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000187:drug effects; D000099252:Fatty Acid Amide Hydrolases
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000581:Amidohydrolases; D001549:Benzamides; D002219:Carbamates; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D019275:Radiopharmaceuticals; D000099252:Fatty Acid Amide Hydrolases; C501412:Abcg2 protein, mouse; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C095122:multidrug resistance protein 3
FAAH; PET; [11C]MPPO; fatty acid amide hydrolase; radiotracer