Organic Synthesis of Potent and Selective Indol-3-yl-oxoacetamides for PET Imaging of Cannabinoid Receptor Type 2
Final Report Abstract
The synthesis of the originally chosen compound 5 was performed. We managed to improve its lipophilicity by substituting the indole W-pentyl chain with ethers of various lengths. However, in our binding assay methods, the lead molecule 5 proved to have a ~20 fold lower affinity than reported in the literature (Ki(CB2) = 8.5 nM vs. 0.37 nM), towards CB2 receptor. Within the newly synthesized derivatives, the fluorine containing compound JHU94150 (16) retained the reported lead’s molecule affinity toward CB2 receptors (Ki(CB2) = 6.2 nM vs. 8.5 nM). However, due to the low density of CB2 in the brain, a radiotracer with subnanomolar affinity is needed. In our hands, this type of compounds proved to be unsuitable for the development of a radiotracer for CB2 imaging in the brain with PET, mainly due the high lipophilicity and low CB2 affinity. We decided to go further with a structurally different, highly affine and selective CB2 ligand A-836339 (38) which has already been radiolabelled with 11C in Horti’s lab. On one hand, some modifications were performed at the cyclopropane subunit, but much more work needs to be done for a better understanding of the medicinal chemistry purpose of this partial structure. In parallel we investigated the scope of the thiazole W-alkyl chain by varying its length and the degree and position of oxygen atoms. Within the synthesized derivatives, we were able to identify compounds 40, 41, 43, 44, 48 and 49 with <1nM affinity towards CB2 receptors, and selectivity CB1/CB2 >100. This study lead to the discovery of JHU94620, a fluorinated compound with excellent CB2 affinity (Ki(CB2) = 0.39 nM) and selectivity (CB1/CB2 ~1000). Upon the completion of the fellowship at the Johns Hopkins University, a radiolabelling precursor for JHU94620 has been synthesized and currently labelling with 18F and the first in vivo experiments are being performed in both Leipzig and JHU labs. It is worthwhile to mention, that for the two different classes of molecules discussed in this work (indole 5 and thiazole A-836339), the presence or absence of the ether groups in the W-alkyl chain has nearly no influence on the CB2 affinity. This interesting finding might be used and tested in the future, when designing new CB2 ligands, for a more facile assessment of the investigated molecules.
