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

Martha Sahylí Ortega Pijeira,Philip H Elsinga,Arian Pérez Nario,Sofia Nascimento Dos Santos,Zhengxing Zhang,Kuo-Shyan Lin,Walter Miguel Turato,Ivone Carvalho,Efrain Araujo Perini,Paulo Sérgio Gonçalves Nunes,Roger Chammas,Emerson Soares Bernardes,Zalua Rodríguez Riera

doi:10.3390/molecules25081872

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 (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 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.

Highlights

Angiotensin II (ANG II) is the effector peptide that exerts most of the physiological functions of the renin-angiotensin system (RAS), and binds with high affinity to two G-protein coupled receptors: angiotensin II type 1 (AT1 ) and angiotensin II type 2 (AT2 ) receptors
Several AT1 R radioligands have been designed, synthesized and evaluated for molecular imaging of AT1 receptors [15,16,17,18,19,20,21,22,23,24]. Most of these AT1 R radioligands (Figure 1), mostly derivatives from commercial angiotensin receptor blockers (ARBs), were labeled with 11 C which is a drawback in the clinic practice due to the very short half-life of 20.4 min [25]
Compared to 11 C, 18 F has a lower maximum energy of the emitted positron of 635 keV, which favors the spatial resolution of positron emission tomography (PET) images [25,26,27], and a higher half-life of 110 min [25] allowing the performance of PET studies without the need of an on-site cyclotron

Summary

Introduction

Angiotensin II (ANG II) is the effector peptide that exerts most of the physiological functions of the renin-angiotensin system (RAS), and binds with high affinity to two G-protein coupled receptors: angiotensin II type 1 (AT1 ) and angiotensin II type 2 (AT2 ) receptors. PET imaging uses radiopharmaceuticals labelled with positron-emitting radioisotopes such as carbon-11. Several AT1 R radioligands have been designed, synthesized and evaluated for molecular imaging of AT1 receptors [15,16,17,18,19,20,21,22,23,24] Most of these AT1 R radioligands (Figure 1), mostly derivatives from commercial angiotensin receptor blockers (ARBs), were labeled with 11 C which is a drawback in the clinic practice due to the very short half-life of 20.4 min [25]. Compared to 11 C, 18 F has a lower maximum energy of the emitted positron of 635 keV, which favors the spatial resolution of PET images [25,26,27], and a higher half-life of 110 min [25] allowing the performance of PET studies without the need of an on-site cyclotron. To the best of our knowledge, just one 18 F-labelled losartan-based

Methods

Results

Discussion

Conclusion