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J Nucl Med. 2008; 49 (Supplement 1):141P
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Radiopharmaceutical Chemistry: New Chemistry-Neurosciences

Radiotracers - Receptors and Transporters

Synthesis and evaluation of a carbon-11 labeled 2-oxoquinoline derivative as a PET radioligand with affinity for the CB2 receptor

N. Evens1, G. Muccioli2, D. Lambert2, P. Vermaelen1, K. Van Laere1, A. Verbruggen1 and G. Bormans1

1 Lab. Radiopharm. Nucl. Med., K.U. Leuven, Leuven, Belgium; 2 Dep. Pharm. Chem. Radiopharm., U.C. Louvain, Leuven, Belgium

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Objectives: Two cannabinoid receptors (CB1R and CB2R) have been identified so far. CB2R is mainly distributed in cells related to the immune system and upregulation of CB2R has been reported in various pathological conditions. At this moment, no PET tracer is available to study CB2R in vivo. The aim of this study was the development and evaluation of 7-[11C]methoxy-2-oxo-8-butyloxy-1,2-dihydroquinoline-3-carboxylic acid cyclohexylamide (1) as a potential CB2R tracer agent.

Methods: The stable reference compound (2) was synthesized based on literature methods [1] and its affinity and selectivity for CB2R were determined. (2) was demethylated to 7-hydroxy-2-oxo-8-butyloxy-1,2-dihydroquinoline-3-carboxylic acid cyclohexylamide (3) by treatment with lithium diphenylphosphide. Labeling of (3) was done by heating 200 µg (3) with [11C]CH3I in 200 µl DMF at 90°C for 2 min in the presence of Cs2CO3. The log Poct/buff, biodistribution and metabolism of (1) in normal mice were studied.

Results: Precursor (3) was synthesized with a 26 % yield and radiolabeled with a 25 % yield. The logP of (1) was ~ 3.5. (1) shows high brain uptake (1.5 % of ID 2 min pi) and a fast brain clearance (0.3 % of ID 60 min pi). Excretion proceeds mainly through the hepatobiliary pathway. Plasma metabolite studies showed 68 % and 17 % (1), 2 min and 30 min pi resp. (2) has a high affinity for hCB2R (KihCB2 = 9.6 nM) and high selectivity compared to hCB1R (KiCB1 > 1000 nM).

Conclusions: (2) was successfully demethylated and converted to (1). (1) showed efficient passage over the BBB. In view of the high and selective affinity for human CB2R, (1) will be further evaluated as a PET tracer for the visualisation of CB2R expression.





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Right arrow Articles by Bormans, G.