MC225, a novel probe for P-glycoprotein PET Imaging at the blood-brain barrier: in vitro cardiovascular safety evaluation

The P-glycoprotein (P-gp) substrate MC225, at concentrations ≤ 10 nM, is a valuable radiotracer for positron emission tomography (PET) imaging of P-gp function in rats and mice.The aim of this study was to evaluate its potential toxic hazard towards the cardiovascular system through an in-depth analysis of its effects on rat aorta rings, on CaV1.2 channel current (ICa1.2) of A7r5 cells and on Langendorff perfused rat heart.In aortic rings, MC225 relaxed phenylephrine-induced contraction in a concentration-dependent and endothelium-independent manner, with an IC50 value of about 1 µM. At concentrations ≥ 3 µM, it antagonized the response to cumulative concentrations of K. MC225, 1 µM and 10 µM, inhibited ICa1.2 by 15% and 31%, respectively, without affecting either current activation, or inactivation kinetics.In Langendorff perfused rat hearts, only 10 µM MC225 significantly decreased left ventricular pressure and increased coronary perfusion pressure while reducing heart rate and prolonging the cardiac cycle length as well as the PQ interval on the ECG. Lower concentrations of the drug were ineffective.These findings demonstrate that MC225-induced cardiovascular effects took place at concentrations that are at least two orders of magnitude higher than those allowing in vivo measurement of P-gp function. Therefore, MC225 represents a promising PET tool for in vivo straightforward P-gp quantification.