Synthesis and Evaluation of [¹⁸F]FEtLos and [¹⁸F]AMBF₃Los as Novel ¹⁸F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors.

ABSTRACT: Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT₁Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT₁R 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, [¹⁸F]fluoroethyl-losartan ([¹⁸F]FEtLos) and [¹⁸F]ammoniomethyltrifluoroborate-losartan ([¹⁸F]AMBF₃Los). [¹⁸F]FEtLos was radiolabeled by ¹⁸F-fluoroalkylation of losartan potassium using the prosthetic group 2-[¹⁸F]fluoroethyl tosylate; whereas [¹⁸F]AMBF₃Los was prepared following an one-step ¹⁸F-¹⁹F 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 AT₁R-expressing membranes showed that AMBF₃Los 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 [¹⁸F]AMBF₃Los displayed a good binding affinity for AT₁R-overexpressing CHO cells and was able to specifically bind to renal AT₁R. Hence, our data demonstrate [¹⁸F]AMBF₃Los as a new tool for PET imaging of AT₁R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.

SUBMITTER: Sahyli Ortega Pijeira M 

PROVIDER: S-EPMC7221519 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature