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

Abstract

Most physiologic effects of the renin angiotensin system (RAS) are mediated via the angiotensin (Ang) type 1 receptor (AT 1 R). The 18 FFPyKYNE derivative of the clinically used AT 1 R blocker losartan exhibits high binding selectivity for kidney AT 1 R and rapid metabolism in rats. The aim of this study was to further assess the binding profile of this novel PET agent for imaging AT 1 R in rats and pigs. Methods: In vitro binding assays were performed with 18 F-FPyKYNElosartan 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. Testretest PET imaging, blocking with AT 1 R antagonist candesartan (10 mg/kg), and plasma metabolism analysis were performed in female Yorkshire pigs. Results: 18 F-FPyKYNE-losartan bound with high affinity (dissociation constant of 49.4 ± 18.0 nM and maximal binding of 348 ± 112 fmol/mm 2 ) to rat kidney AT 1 R. It bound strongly to plasma proteins in rats (97%), and its labeled metabolites displayed minimal interference on renal AT 1 R 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. Conclusion: 18 F-FPyKYNE-losartan has a favorable binding profile and displays high potential for translational work in humans as an AT 1 R PET imaging agent.

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

“…2-[ 18 F]fluoro-3-pent-4-yn-1-yloxypyridine ([ 18 F]FPyKYNE)-losartan was the first and only 18 F-labeled losartan analog reported to date, to the best of our knowledge, synthetized by click chemistry. This radioligand showed high binding selectivity to renal AT 1 R in both rats and (Arksey et al, 2014;Hachem et al, 2016).…”

“…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).…”

“…This radioligand was synthetized using a copper (I)-catalyzed click reaction between the correspondent 18 F-labeled terminal alkyne and azide-modified tetrazole-protected losartan, and followed by acidic deprotection and HPLC purification (Arksey et al, 2014). In vitro saturation binding studies showed that [ 18 F]FPyKYNE-losartan bound with high affinity to the renal cortex AT 1 R (with a dissociation constant of 49.4 nM and maximal binding of 348±112 fmol/mm 2 ) (Hachem et al, 2016). Additionally, PET imaging of rats and pigs with [ 18 F]FPyKYNE-losartan exhibited a high tissue contrast in kidneys with slow clearance and binding selectivity for renal AT 1 R (Arksey et al, 2014;Hachem et al, 2016).…”

“…In vitro saturation binding studies showed that [ 18 F]FPyKYNE-losartan bound with high affinity to the renal cortex AT 1 R (with a dissociation constant of 49.4 nM and maximal binding of 348±112 fmol/mm 2 ) (Hachem et al, 2016). Additionally, PET imaging of rats and pigs with [ 18 F]FPyKYNE-losartan exhibited a high tissue contrast in kidneys with slow clearance and binding selectivity for renal AT 1 R (Arksey et al, 2014;Hachem et al, 2016). However, the tracer antagonized the ANG II pressor effect with 4-fold potency reduction relative to losartan (Hachem et al, 2016).…”

“…Additionally, PET imaging of rats and pigs with [ 18 F]FPyKYNE-losartan exhibited a high tissue contrast in kidneys with slow clearance and binding selectivity for renal AT 1 R (Arksey et al, 2014;Hachem et al, 2016). However, the tracer antagonized the ANG II pressor effect with 4-fold potency reduction relative to losartan (Hachem et al, 2016).…”