Synthesis and Evaluation of [(18)F]FEtLos and [(18)F]AMBF(3)Los as Novel (18)F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors.

Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT(1)Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT(1)R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [(18)F]fluoroethyl-losartan ([(18)F]FEtLos) and [(18)F]ammoniomethyltrifluoroborate-losartan ([(18)F]AMBF(3)Los). [(18)F]FEtLos was radiolabeled by (18)F-fluoroalkylation of losartan potassium using the prosthetic group 2-[(18)F]fluoroethyl tosylate; whereas [(18)F]AMBF(3)Los was prepared following an one-step (18)F-(19)F isotopic exchange reaction, in an overall yield of 2.7 ± 0.9% and 11 ± 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT(1)R-expressing membranes showed that AMBF(3)Los presented an almost equivalent binding affinity (K(i) 7.9 nM) as the cold reference Losartan (K(i) 1.5 nM), unlike FEtLos (K(i) 2000 nM). In vitro and in vivo assays showed that [(18)F]AMBF(3)Los displayed a good binding affinity for AT(1)R-overexpressing CHO cells and was able to specifically bind to renal AT(1)R. Hence, our data demonstrate [(18)F]AMBF(3)Los as a new tool for PET imaging of AT(1)R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.