Analysis of [11C]methyl-candesartan kinetics in the rat kidney for the assessment of angiotensin II type 1 receptor density in vivo with PET

Lortie, Mireille; DaSilva, Jean N.; Kirkpatrick, Sheryn A.; Hadizad, Tayebeh; Ismail, Basma; deKemp, Robert A.

doi:10.1016/j.nucmedbio.2012.10.013

Cited by 15 publications

(14 citation statements)

References 18 publications

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“…Unchanged 18 FFPyKYNE-losartan was added to plasma obtained from rats (n 5 5) sacrificed by decapitation without anesthesia. Plasma was centrifuged (2,000g, 30 min) and the filtrate (protein-free fraction) counted in the g-counter (18,19).…”

Section: Rat Studiesmentioning

confidence: 99%

“…During the PET scans, blood samples were collected from the femoral artery at 25 (control), 1, 2, 5, 10, 20, and 40 min after injection (n 5 3). Plasma samples were prepared as described previously (11,19). Control plasma was spiked with 0.37 MBq of tracer, filtered, and then injected onto the HPLC system.…”

Section: Rat Studiesmentioning

confidence: 99%

“…Blood samples were weighed and counted for activity. Samples were centrifuged to obtain plasma and then weighed and counted to determine activity per gram (19). (paired or unpaired).…”

Section: Rat Studiesmentioning

confidence: 99%

“…(paired or unpaired). The test-retest variability was calculated by taking the ratio of the absolute value of the difference between repeated measurements and the mean of the repeated measurements as described by Lortie et al (19).…”

Section: Rat Studiesmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Rat Studiesmentioning

confidence: 99%

Section: Rat Studiesmentioning

confidence: 99%

“…Blood samples were weighed and counted for activity. Samples were centrifuged to obtain plasma and then weighed and counted to determine activity per gram (19). (paired or unpaired).…”

Section: Rat Studiesmentioning

confidence: 99%

Section: Rat Studiesmentioning

confidence: 99%

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

et al. 2016

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“…3 modeling was performed with [ 11 C]methyl-candesartan only [12]. However to date, no 11 Clabeled AT 1 R PET tracers have demonstrated proper kinetics, and appropriate metabolism/stability to bring them to clinical setup.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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

Ismail

Hadizad

Antoun

et al. 2015

Nuclear Medicine and Biology

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

et al. 2018

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The renin angiotensin aldosterone system (RAAS) is a hormonal cascade involved in the regulation of blood pressure and electrolyte balance, and represents a common target for the treatment of various diseases including hypertension, heart failure, and diabetes. Herein we present a novel 18F‐labeled derivative of the drug irbesartan, one of the most prescribed angiotensin II type 1 receptor (AT1R) antagonists, for in vivo positron emission tomography (PET). This allows the in vivo measurement of AT1R expression, and thus the evaluation of functional changes in its expression under pathophysiological conditions. We followed various synthetic approaches optimized for the introduction of fluorine into different positions of the aliphatic side chain of irbesartan. Radioligand binding studies revealed that fluorine atoms at specified positions (α‐position (IC50=6.6 nm) and δ‐position (IC50=8.5 nm) of the aliphatic side chain) do not alter the binding properties of irbesartan (IC50=1.6 nm). After successful radiolabeling with fluorine‐18 in a radiochemical yield of 11 %, we observed high renal uptake in healthy rats and pigs, which could be decreased by pretreatment with the parent compound irbesartan.

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Analysis of [11C]methyl-candesartan kinetics in the rat kidney for the assessment of angiotensin II type 1 receptor density in vivo with PET

Cited by 15 publications

References 18 publications

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

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

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

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

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Analysis of [11C]methyl-candesartan kinetics in the rat kidney for the assessment of angiotensin II type 1 receptor density in vivo with PET

Cited by 15 publications

References 18 publications

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

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

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

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

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Product

Resources

About

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

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

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