J Nucl Med. 2008; 49 (Supplement 1):129P
Neurosciences: Basic ScienceEmerging Ligands and Targets |
Synthesis and in vitro and vivo evaluation of new analogs of [11C]JHU75528 for imaging of cerebral (CB1) cannabinoid receptors
Hong Fan1,
Hayden Ravert1,
Daniel Holt1,
Paige Finley1,
Ursula Scheffel1,
Robert Dannals1 and
Andrew Horti1
1 Radiology, Johns Hopkins Medicine, Baltimore, Maryland
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Objectives: To obtain a PET radioligand with improved CB1 in vivo binding properties (higher target-to-non-target ratio, %ID/g tissue) compared to [11C]JHU75528 ([11C]OMAR)
Methods: A series of CB1 ligands, analogs of 4-cyano-1-(2,4-dichlorophenyl)-5-(4-[11C]methoxyphenyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide ([11C]JHU75528), with high in vitro binding affinities was synthesized. The lipophilicity values (logD7.4) were also determined. 11C-radiolabeling of the ligands was performed with [11C]methyltriflate. Regional distribution studies in the mouse brain were performed with selected radioligands.
Results: A series of CB1 ligands with a range of binding affinities (Ki=2-1000 nM) and lipophilicities (logD7.4=2.5-3.5) was synthesized in good yield. The best member of the series, 4-cyano-1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-N-alkyl-1H-pyrazole-3-carboxamide (JHU76609), exhibited an improved combination of Ki and logD7.4 values over the previously reported JHU75528. JHU76609 was radiolabeled with 11C with a radiochemical yield 15-24%, specific radioactivity 482±288 GBq/µmol and radiochemical purity greater than 98%. In mice studies, [11C]JHU76609 displayed a higher hippocampus/brainstem ratio (3.5) than [11C]JHU75528, whereas the previously developed [11C]JHU75575 exhibited comparable properties to [11C]JHU75528.
Conclusions: The novel PET radioligand [11C]JHU76609 holds promise for quantitative PET imaging studies of cerebral CB1 receptors.
Research Support: JHU Radiology, NIH grant (R21MH079017)
