Characterization of R-[11C]rolipram for PET imaging of phosphodiesterase-4: in vivo binding, metabolism, and dosimetry studies in rats

Lourenço, Célia; Houle, Sylvain; Wilson, Alan A.; DaSilva, Jean N.

doi:10.1016/s0969-8051(01)00206-2

Cited by 36 publications

(42 citation statements)

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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%

“…Conflicting results have been reported on AT 1 R levels measured under pathophysiologic conditions. Although previous PET studies have been performed with small (rodents) and larger (dogs, baboons, pigs) animals (4-6) using 11 C-labeled AT 1 R ligands, no research has been published using an 18 F-labeled AT 1 R ligand. 18 F-labeled tracers offer some key advantages over 11 C, including a longer half-life (109.6 vs. 20.4 min) (7), enabling multiple scans from a single formulation and shipment to other sites and higher image resolution due to lower energy and shorter positron range (0.23 vs. 0.39 mm in soft tissue) (8), thus enabling higher image resolution.…”

mentioning

confidence: 99%

“…Moreover, addition of a leucine and a short linker composed of tetraethylene glycol and diglycolic acid between the losartan moiety and the tetra-amine chelator yielded to a losartan analog displaying high affinity (inhibitory constant 5 6 nmol/L) for AT 1 R (10). Recently, 18 F-FPyKYNE-losartan was synthesized by conjugation of 18 F-FPyKYNE with the azide-modified trityl losartan via click chemistry with high chemical and radiochemical purities (11). Preliminary in vivo evaluation of 18 F-FPyKYNE-losartan with PET imaging displayed a dose-dependent reduction of this radiotracer in rat kidney AT 1 Rs and binding selectivity for AT 1 R over AT 2 R. Additionally, 18 F-FPyKYNE-losartan is metabolized into mostly hydrophilic-labeled products in rat plasma, suggesting minimal interference of the 18 F-labeled metabolites with AT 1 R binding (11).…”

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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%

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

et al. 2016

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“…Biodistribution studies were performed in conscious animals as described previously (19). Briefly, 51.8-74 MBq (1.4-2.0 mCi at time of first injection) of HED were injected as a 0.1-to 0.3-mL bolus into the lateral tail vein of each restrained rat.…”

Section: Ex Vivo Biodistributionmentioning

confidence: 99%

“…Heart (n 5 3), brown adipose tissue (n 5 4), and pancreas (n 5 3) were rapidly dissected and a plasma sample (n 5 6) was obtained from centrifuged blood (3,000g, 4,000 rpm, 5 min). Tissues were processed for injection on the HPLC system as described previously (19). Briefly, samples were homogenized in 80:20 ethanol/water (v/v) using a Polytron tissue homogenizer.…”

Section: Plasma and Tissue Radiolabeled Metabolite Analysismentioning

confidence: 99%

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

Thackeray¹,

Beanlands²,

DaSilva³

2007

Journal of Nuclear Medicine

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11 C-meta-Hydroxyephedrine (HED) is used in cardiac PET as an index of norepinephrine (NE) reuptake transporter (NET) density and synaptic NE levels. Whereas cardiac uptake is well documented, tracer retention in other tissues with rich noradrenergic innervation is unclear. Dysfunctional sympathetic nervous system (SNS) function in extracardiac metabolic storage tissues (i.e., adipose tissue and skeletal muscle) and endocrine organs contributes to several disorders. The aim of this study was to determine the potential of HED as an index of NE function in brown adipose tissue, lung, pancreas, skeletal muscle, and kidney by identifying NET-specific retention and determining the presence of radiolabeled metabolites. Methods: Male Sprague-Dawley rats were administered HED and sacrificed at 30 min after tracer injection. Tissues were rapidly excised and counted for radioactivity, and relative tracer retention was quantified. Pretreatment with NET inhibitors established specific HED accumulation. The effect of elevated NE was tested by subcutaneous minipump NE infusion or inhibition of monoamine oxidase. Column-switch high-performance liquid chromatography (HPLC) was used to analyze the presence of radiolabeled metabolites in heart, brown adipose tissue, pancreas, and plasma. Results: NET-specific retention was observed in heart, brown adipose tissue, lung, and pancreas but not in liver, skeletal muscle, or kidney. A dosedependent response of HED accumulation to treatments elevating NE levels was established in tissues exhibiting specific uptake. At 30 min after tracer administration, HPLC analysis revealed 93%-95% of total radioactivity signal derived from unchanged HED in heart, pancreas, and brown adipose tissue compared with 61% 6 8% unchanged HED in plasma. Conclusion: In addition to the heart, lung, pancreas, and brown adipose tissue exhibit specific and NE-responsive uptake of HED, supporting the potential for novel PET studies of SNS integrity in these tissues.Key Words: sympathetic nervous system function; norepinephrine transporter uptake-1; competition with norepinephrine; HPLC column-switch system The sympathetic nervous system (SNS) is a primary extrinsic control mechanism mediating cardiac function, metabolic processes, and adaptation to stress. In normal conditions, the neurotransmitter norepinephrine (NE) is released from the presynaptic bouton into the synapse, where it binds to and stimulates adrenoceptors on pre-and postsynaptic cells. Excess NE is recycled into the presynaptic neuron by active transport via the uptake-1 NE reuptake transporter (NET) (1,2).In myocardium, the SNS modulates heart rate, cardiac output, and stroke volume (2). In metabolic storage tissues, SNS activation stimulates 2 key processes: lipolysis-the breakdown of lipids primarily in white adipocytes-and thermogenesis-the uncoupling of mitochondrial energetics promoting heat release over energy storage, primarily in brown adipocytes and skeletal muscle (3). The SNS also partially controls pancreatic secretion of insulin and gl...

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A Comparative Study of in vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in vivo

et al. 2019

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Nonspecific binding (NSB) is a key parameter in optimizing PET imaging tracers. We compared the ability to predict NSB of three available methods: LIMBA, rat fu,brain, and CHI(IAM). Even though NSB is often associated with lipophilicity, we observed that logD does not correlate with any of these assays, clearly indicating that lipophilicity, while influencing NSB, is insufficient to predict it. A cross‐comparison of the methods showed that all three correlate and are useful predictors of NSB. The three assays, however, rank the molecules slightly differently, illustrating the challenge of comparing molecules within a narrow chemical space. We also noted that CHI(IAM) values more effectively predict VNS, a measure of in vivo NSB in the human brain. CHI(IAM) measurements might be a closer model of the actual physicochemical interaction between PET tracer candidates and cell membranes, and seems to be the method of choice for the optimization of in vivo NSB.

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Characterization of R-[11C]rolipram for PET imaging of phosphodiesterase-4: in vivo binding, metabolism, and dosimetry studies in rats

Cited by 36 publications

References 28 publications

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

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

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

A Comparative Study of in vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in vivo

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Characterization of R-[11C]rolipram for PET imaging of phosphodiesterase-4: in vivo binding, metabolism, and dosimetry studies in rats

Cited by 36 publications

References 28 publications

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

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

Presence of Specific 11C-meta-Hydroxyephedrine Retention in Heart, Lung, Pancreas, and Brown Adipose Tissue

A Comparative Study of in vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in vivo

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

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