Novel ¹⁸F-Labeled PET Imaging Agent FV45 Targeting the Renin–Angiotensin System

Abstract

Renin–angiotensin system (RAS) plays an important role in the regulation of blood pressure and hormonal balance. Using positron emission tomography (PET) technology, it is possible to monitor the physiological and pathological distribution of angiotensin II type 1 receptors (AT1), which reflects the functionality of RAS. A new 18F-labeled PET tracer derived from the clinically used AT1 antagonist valsartan showing the least possible chemical alteration from the valsartan structure has been designed and synthesized with several strategies, which can be applied for the syntheses of further derivatives. Radioligand binding study showed that the cold reference FV45 (Ki 14.6 nM) has almost equivalent binding affinity as its lead valsartan (Ki 11.8 nM) and angiotensin II (Ki 1.7 nM). Successful radiolabeling of FV45 in a one-pot radiofluorination followed by the deprotection procedure with 21.8 ± 8.5% radiochemical yield and >99% radiochemical purity (n = 5) enabled a distribution study in rats and opened a path to straightforward large-scale production. A fast and clear kidney uptake could be observed, and this renal uptake could be selectively blocked by pretreatment with AT1-selective antagonist valsartan. Overall, as the first 18F-labeled PET tracer based on a derivation from clinically used drug valsartan with almost identical chemical structure, [18F]FV45 will be a new tool for assessing the RAS function by visualizing AT1 receptor distributions and providing further information regarding cardiovascular system malfunction as well as possible applications in inflammation research and cancer diagnosis.

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

“…PET imaging uses radiopharmaceuticals labelled with positron-emitting radioisotopes such as carbon-11 ( 11 C) and fluorine-18 ( 18 F). Several AT 1 R radioligands have been designed, synthesized and evaluated for molecular imaging of AT 1 receptors [15][16][17][18][19][20][21][22][23][24]. Most of these AT 1 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].…”

“…Therefore, we designed the novel analog [ 18 F]fluoroethyl-losartan ([ 18 F]FEtLos; Figure 2) following a similar reaction scheme to the one reported for [ 11 C]methyl-losartan ( Figure 1). [15][16][17][18][19][20][21][22][23][24]. Therefore, here we described the synthesis and 18 F-labeling of two novel losartan derivatives using less hydrophobic motifs such as: 2-fluoroethoxy and ammoniomethyltrifluoroborate (AMBF3), [ 18 F]FEtLos and [ 18 F]AMBF3Los, respectively ( Figure 2).…”

Synthesis of fluorine-18-labeled losartan analogs as novel positron emission tomography tracers for cancer imaging

“…Competitive binding assays revealed similar binding affinity between the cold FV45 (14.6 ± 10.0 nM) and the antagonist valsartan (11.8 ± 3.4 nM); the µPET/CT imaging in control rats showed a fast clearance and specific kidney uptake which was reduce after pretreatment with the AT 1 R blocker valsartan (Chen et al, 2018).…”

“…Several AT 1 R PET ligands have been radiolabeled with 11 C and 18 F ( Figure 5), and evaluated in animals (mice, rats, dogs, baboon, pigs, rhesus macaques) and humans (Szabo et al, 1998;Mathews et al, 2004;Zober et al, 2006;Hadizad et al, 2009;Mathews e Szabo, 2010;Iimori et al, 2011;Chopra, 2012;Noda et al, 2012;Gulaldi et al, 2013;Lortie et al, 2013;Arksey et al, 2014;Ismail et al, 2015;Hachem et al, 2016;Chen et al, 2018).…”

“…[ 18 F]FV45 was prepared in 120 minutes by one-pot nucleophilic 18 F-fluorination and followed by deprotection procedure and HPLC purification (Chen et al, 2018).…”