[¹¹C]Methyl‐losartan as a potential ligand for PET imaging angiotensin II AT₁ receptors

Abstract

The renin-angiotensin system regulates blood pressure via activation of the angiotensin II type 1 receptor (AT 1 R). The AT 1 R is involved in the pathology of cardiac and renal diseases such as heart failure and diabetic nephropathy. The aim of this study was to synthesize and characterize the O-[ 11 C]methylated derivative of the clinically used AT 1 receptor blocker losartan as a novel AT 1 R PET imaging radioligand. [ 11 C]Methyl-losartan was reliably synthesized (n≥40) via methylation of tetrazoleprotected losartan followed by deprotection using HCl in an overall yield of 30%-60% (decay-corrected from [11 C]MeI). Radiochemical purity was >99% and specific activity 700-3600mCi/mmol.

Evaluation of [11C]methyl-losartan and [11C]methyl-EXP3174 for PET imaging of renal AT1receptor in rats

“…A similar approach to the production of [ 11 C]methyl-losartan [13] was used for the synthesis of [ 11 C]methyl-EXP3174. The 1 H-NMR spectrum demonstrated disappearance of the trityl peaks in aromatic region and appearance of a broad singlet at 13.40-11.80 ppm corresponding to a proton of the tetrazole group.…”

“…In attempt to increase tracer retention for renal AT 1 R, [ 11 C]methyl-losartan was recently synthesized by O-[ 11 C]methylation of the clinically used ARB, losartan [13]. Losartan is biotransformed by the liver cytochrome P450 system mainly to the active carboxylic acid derivative, EXP3174 that is considered to be responsible for most of its pharmacological effects [14][15][16].…”

“…1) was produced reliably by O-[ 11 C]methylation followed by acid removal of the trityl protecting group as described previously [13].…”

18F‐Labeled Derivatives of Irbesartan for Angiotensin II Receptor PET Imaging

“…These drugs are well established in therapy and exhibit desirable properties regarding affinity, selectivity, drug safety, and metabolic stability with a low chance for radioactive metabolites giving unspecific activity. At this point, only a small number of sartan‐based radioligands have been reported . The most developed compound is [ 11 C]KR31173 ( 5 ), which is a methoxy derivative of the non‐peptide AT 1 R antagonist SK‐1080 ( 4 ) .…”

“…These drugs are well established in therapy and exhibit desirable properties regarding affinity,s electivity,d rug safety,a nd metabolic stability with al ow chance for radioactive metabolites giving unspecific activity.A t this point, only as mall number of sartan-based radioligands have been reported. [17][18][19] The most developed compound is [ 11 C]KR31173 (5), which is amethoxy derivativeo fthe non-peptide AT 1 Ra ntagonist SK-1080 (4). [20] This ligand has been studied in several animal models of kidney andh eart diseases and has also been studied in the first humant rial,w hich demonstrated myocardial retention of the PET tracer.…”