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. 2013 Jan 10;56(1):201-9.
doi: 10.1021/jm301492y. Epub 2012 Dec 19.

Radiosynthesis and evaluation of [¹¹C-carbonyl]-labeled carbamates as fatty acid amide hydrolase radiotracers for positron emission tomography

Alan A Wilson  1 , Justin W Hicks, Oleg Sadovski, Jun Parkes, Junchao Tong, Sylvain Houle, Christopher J Fowler, Neil Vasdev
Affiliations
Free PMC article

Radiosynthesis and evaluation of [¹¹C-carbonyl]-labeled carbamates as fatty acid amide hydrolase radiotracers for positron emission tomography

Alan A Wilson et al. J Med Chem. .
Free PMC article

Abstract

Fatty acid amide hydrolase (FAAH) plays a key role in regulating the tone of the endocannabinoid system. Radiotracers are required to image and quantify FAAH activity in vivo. We have synthesized a series of potent FAAH inhibitors encompassing two classes of N-alkyl-O-arylcarbamates and radiolabeled eight of them with carbon-11. The [¹¹C-carbonyl]-radiotracers were evaluated in vitro and ex vivo in rats as potential FAAH imaging agents for positron emission tomography (PET). Both sets of [¹¹C]O-arylcarbamates showed good to excellent brain penetration and an appropriate regional distribution. Pretreatments with a FAAH inhibitor demonstrated that 80-95% of brain uptake of radioactivity constituted binding of the radiotracers to FAAH. Brain extraction measurements showed that binding to FAAH was irreversible and kinetically different for the two classes of carbamates. These promising results are discussed in terms of the requirements of a suitable radiotracer for the in vivo imaging of FAAH using PET.

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Figures

Scheme 1
Scheme 1. Synthesis of O-Arylcarbamates Studied as FAAH Inhibitors
Reagents and conditions: (a) TEA, CH3CN, 90 min; (b) (i) COCl2, toluene, 0 °C to ambient, 30 min, (ii) R-NH2, TEA, CH3CN, 30 min, (iii) 10%Pd/C, ammonium formate, MeOH, reflux, 15 min; (c) (i) 4-nitrophenylchloroformate, DIPEA, DCM, 30 min, (ii) R-NH2, 1 h.
Scheme 2
Scheme 2. Synthesis of Benzyl Protected Dihydroquinone, 14
Scheme 3
Scheme 3. Radiosynthesis of [11C-Carbonyl]O-arylcarbamates and Their Subsequent Tagging of FAAH
Figure 1
Figure 1
Regional uptake of radioactivity in rat brain of two representative [11C]-radiotracers at 2 and 40 min post iv injection. (A, left): [11C]7; (B, right): [11C]3. The blocked groups were pretreated with compound 2 (2 mg/kg, ip). Each value represents the mean (n = 5) ± SD.
Figure 2
Figure 2
Amounts of radioactivity irreversibly bound to rat brain parenchyma postintravenous injection of [11C]3 (n = 3–4/group). (A) % bound at various time points. (B) Amount bound at 5 and 40 min postinjection and after pretreatment with compound 2 (2 mg/kg, ip).
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