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

Angiotensin II type 1 receptors (AT₁ R) blocker losartan is used in patients with renal and cardiovascular diseases. [¹⁸ F]fluoropyridine-losartan has shown favorable binding profile for quantitative renal PET imaging of AT₁ R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [¹⁸ F]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 [¹⁸ F]FPyKYNE was obtained by radiofluorination of NO₂ PyKYNE 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 [¹⁸ F]fluoropyridine-losartan in 11 ± 2% (decay-corrected from [¹⁸ F]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 [¹⁸ F]FPyKYNE to the unprotected losartan azide afforded [¹⁸ F]fluoropyridine-losartan in similar yields (11 ± 3%, decay-corrected from [¹⁸ F]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 AT₁ R expression in several diseases.

Cu(I) stabilizing agent THPTA; CuAAC click chemistry; automation; fluorine-18.