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Media type:
E-Article
Title:
Radiofluorination and biological evaluation of N-aryl-oxadiazolyl-propionamides as potential radioligands for PET imaging of cannabinoid CB2 receptors
Published:
Springer Science and Business Media LLC, 2013
Published in:
Organic and Medicinal Chemistry Letters, 3 (2013) 1
Language:
English
DOI:
10.1186/2191-2858-3-11
ISSN:
2191-2858
Origination:
Footnote:
Description:
AbstractBackgroundThe level of expression of cannabinoid receptor type 2 (CB2R) in healthy and diseased brain has not been fully elucidated. Therefore, there is a growing interest to assess the regional expression of CB2R in the brain. Positron emission tomography (PET) is an imaging technique, which allows quantitative monitoring of very low amounts of radiolabelled compounds in living organisms at high temporal and spatial resolution and, thus, has been widely used as a diagnostic tool in nuclear medicine. Here, we report on the radiofluorination ofN-aryl-oxadiazolyl-propionamides at two different positions in the lead structure and on the biological evaluation of the potential of the two tracers [18F]1and [18F]2as CB2receptor PET imaging agents.ResultsHigh binding affinity and specificity towards CB2receptors of the lead structure remained unaffected by the structural changes such as the insertion of the aliphatic and aromatic fluorine in the selected labelling sites of1and2. Aliphatic and aromatic radiofluorinations were optimized, and [18F]1and [18F]2were achieved in radiochemical yields of ≥30% with radiochemical purities of ≥98% and specific activities of 250 to 450 GBq/μmol. Organ distribution studies in female CD1 mice revealed that both radiotracers cross the blood–brain barrier (BBB) but undergo strong peripheral metabolism. At 30 min after injection, unmetabolized [18F]1and [18F]2accounted for 60% and 2% as well as 68% and 88% of the total activity in the plasma and brain, respectively. The main radiometabolite of [18F]2could be identified as the free acid [18F]10, which has no affinity towards the CB1and CB2receptors but can cross the BBB.ConclusionsN-aryl-oxadiazolyl-propionamides can successfully be radiolabelled with18F at different positions. Fluorine substitution at these positions did not affect affinity and specificity towards CB2R. Despite a promisingin vitrobehavior, a rather rapid peripheral metabolism of [18F]1and [18F]2in mice and the generation of brain permeable radiometabolites hamper the application of these radiotracersin vivo. However, it is expected that future synthetic modification aiming at a replacement of metabolically susceptible structural elements of [18F]1and [18F]2will help to elucidate the potential of this class of compounds for CB2R PET studies.