Characterization of 18F-FPyKYNE-Losartan for Imaging AT1 Receptors

Most physiologic effects of the renin angiotensin system (RAS) are mediated via the angiotensin (Ang) type 1 receptor (AT₁R). The ¹⁸F-FPyKYNE derivative of the clinically used AT₁R blocker losartan exhibits high binding selectivity for kidney AT₁R and rapid metabolism in rats. The aim of this study was to further assess the binding profile of this novel PET agent for imaging AT₁R in rats and pigs.

In vitro binding assays were performed with ¹⁸F-FPyKYNE-losartan in rat kidneys. Male Sprague-Dawley rats were used to assess dosimetry, antagonistic efficacy via blood pressure measurements, and presence of labeled metabolites in kidneys. Test-retest PET imaging, blocking with AT₁R antagonist candesartan (10 mg/kg), and plasma metabolism analysis were performed in female Yorkshire pigs.

¹⁸F-FPyKYNE-losartan bound with high affinity (dissociation constant of 49.4 ± 18.0 nM and maximal binding of 348 ± 112 fmol/mm²) to rat kidney AT₁R. It bound strongly to plasma proteins in rats (97%), and its labeled metabolites displayed minimal interference on renal AT₁R binding. FPyKYNE-losartan fully antagonized the Ang II pressor effect, albeit with 4-fold potency reduction (the effective dose inhibiting 50% of the Ang II-induced maximal pressor response of 25.5 mg/kg) relative to losartan. PET imaging exhibited high kidney-to-blood contrast and slow renal clearance, with an SUV of 14.1 ± 6.2. Excellent reproducibility was observed in the calculated test-retest variability (7.2% ± 0.75%). Only hydrophilic-labeled metabolites were present in plasma samples, and renal retention was reduced (-60%) at 10-15 min after blockade with candesartan.

¹⁸F-FPyKYNE-losartan has a favorable binding profile and displays high potential for translational work in humans as an AT₁R PET imaging agent.