[18F]Fluoropyridine‐losartan: A new approach toward human Positron Emission Tomography imaging of Angiotensin II Type 1 receptors

Abstract

Angiotensin II type 1 receptors (AT1R) blocker losartan is used in patients with renal and cardiovascular diseases. [18F]fluoropyridine‐losartan has shown favorable binding profile for quantitative renal PET imaging of AT1R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [18F]fluoropyridine‐losartan in very high molar activity. Automated radiosynthesis was performed in a three‐step, two‐pot, and two‐HPLC‐purification procedure within 2 h. Pure [18F]FPyKYNE was obtained by radiofluorination of NO2PyKYNE and silica‐gel‐HPLC purification (40 ± 9%), preventing the formation of nitropyridine‐losartan in the second step. Conjugation with trityl‐losartan azide via click chemistry, followed by acid hydrolysis, C18‐HPLC purification and reformulation provided [18F]fluoropyridine‐losartan in 11 ± 2% (decay‐corrected from [18F]fluoride, EOB). Using tris[(1‐(3‐hydroxypropyl)‐1H‐1,2,3‐triazol‐4‐yl)methyl]‐amine (THPTA) as a Cu(I)‐stabilizing agent for coupling [18F]FPyKYNE to the unprotected losartan azide afforded [18F]fluoropyridine‐losartan in similar yields (11 ± 3%, decay‐corrected from [18F]fluoride, EOB). Reverse‐phase HPLC was optimized by reducing the pH of the mobile phase to achieve complete purification and high molar activities (467 ± 60 GBq/μmol). The use of radioprotectants prevented tracer radiolysis for 10 h (RCP > 99%). The product passed the quality control testing. This reproducible automated radiosynthesis process will allow in vivo PET imaging of AT1R expression in several diseases.