1. Nucl Med Biol. 2010 Jul;37(5):665-75. Epub 2010 May 6.

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

Wyffels L, Muccioli GG, Kapanda CN, Labar G, De Bruyne S, De Vos F, Lambert DM.

Department of Radiopharmacy, Ghent University, Harelbekestraat 72, 9000 Ghent,
Belgium.

INTRODUCTION: Fatty acid amide hydrolase (FAAH) is part of the endocannabinoid
system (ECS) and has been linked to the aetiology of several neurological and
neuropsychiatric disorders. So far no useful PET or SPECT tracer for in vivo
visualisation of FAAH has been reported. We synthesized and evaluated a
carbon-11-labeled URB597 analogue, biphenyl-3-yl [(11)C]-4-methoxyphenylcarbamate
or [(11)C]-1, as potential FAAH imaging agent. METHODS: The inhibitory activity
of 1 was determined in vitro using recombinant FAAH. Radiosynthesis of [(11)C]-1 
was performed by methylation using [(11)C]-CH(3)I, followed by HPLC purification.
Biological evaluation was done by biodistribution studies in wild-type and FAAH
knock-out mice, and by ex vivo and in vivo metabolite analysis. The influence of 
URB597 pretreatment on the metabolisation profile was assessed. RESULTS:
[(11)C]-1 was obtained in good yields and high radiochemical purity.
Biodistribution studies revealed high brain uptake in wild-type and FAAH
knock-out mice, but no retention of radioactivity could be demonstrated.
Metabolite analysis and URB597 pretreatment confirmed the non-FAAH-mediated
metabolisation of [(11)C]-1. The inhibition mechanism was determined to be
reversible. In addition, the inhibition of URB597 appeared slowly reversible.
CONCLUSIONS: Although [(11)C]-1 inhibits FAAH in vitro and displays high brain
uptake, the inhibition mechanism seems to deviate from the proposed carbamylation
mechanism. Consequently, it does not covalently bind to FAAH and will not be
useful for mapping the enzyme in vivo. However, it represents a potential
starting point for the development of in vivo FAAH imaging tools.


PMID: 20610171 [PubMed - indexed for MEDLINE]