From 18F-MC225 to Conformationally Free Derivatives

Abstract

PET radiotracer [18F]MC225 is in two different clinical trials for imaging P-glycoprotein (P-gp) at the BBB level. This radiotracer permits to evaluate both the inset of neurodegenerative pathologies such as MCI, AD, and PD and the drug resistance of antidepressant drugs. Although these studies are ongoing, it is known that in MCI, AD, and PD the activity and expression of P-gp at the BBB level is lower than in healthy subjects, whereas the activity of the same pump is high in human subjects with resistance to antidepressant therapy. This level of P-gp is measured by PET with [18F]MC225 that displayed high brain uptake in neurodegenerative diseases and low brain uptake in subjects with resistance versus several antidepressant drugs. Starting from the mentioned PET radiotracer, a series of conformationally free derivatives have been synthesized testing the role of isosteric substitution in terms of P-gp interactions. Aryl-(oxy)-derivative 2c showed in vitro higher P-gp activity than MC225 (EC50 = 1.8 μM vs EC50 = 6.35 μM). This result has been corroborated with molecular docking, RMSD, and Rog timeline plot. The results disclosed a class of compounds, among them, 2c could be easily [11C]/[18F] radiolabeled for in vivo studies. Considering the lower lipophilicity of 2c than MC225, this ligand could be radiolabeled for imaging P-glycoprotein function and expression that is involved in several heart failures, where a low log P is an important and prelaminar parameter to drug targeting.