Determination of the Input Function at the Entry of the Tissue of Interest and Its Impact on PET Kinetic Modeling Parameters

Bentourkia, M’hamed

doi:10.1007/s11307-015-0895-8

Cited by 7 publications

(8 citation statements)

References 71 publications

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“…Samples were centrifuged (5 min; 2,054g; 4°C) and the supernatant (200 µL) was gamma-counted for total plasma radioactivity. Additional plasma samples were withdrawn at 0; 5; 10; 15; 30; 60 and 90 min to measure both i) the percentage of parent (unmetabolized) 11 C-buprenorphine using radio-HPLC and a state-of-the-art methodology [33] and ii) the total concentration of buprenorphine in plasma using mass spectrometry, after radioactive decay. The fraction of parent 11 C-buprenorphine in each sample was used to generate the metabolite-corrected arterial input function for pharmacokinetic modeling of each PET experiment (see supplemental material, Fig.…”

Section: Arterial Input Function and Metabolismmentioning

confidence: 99%

Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo

Auvity

Goutal

Caillé

et al. 2021

Neuropsychopharmacol.

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A wide range of buprenorphine doses are used for either pain management or maintenance therapy in opioid addiction. The complex in vitro profile of buprenorphine, with affinity for µ-, δ-and κ-opioid receptors (OR), makes it difficult to predict its dose-related neuropharmacology in vivo. In rats, microPET imaging and pretreatment by OR antagonists were performed to assess the binding of radiolabeled buprenorphine (microdose 11 Cbuprenorphine) to OR subtypes in vivo (n=4 per condition). The µ-selective antagonist naloxonazine (10 mg/kg) and the non-selective OR-antagonist naloxone (1 mg/kg) blocked the binding of 11 C-buprenorphine while pretreatment by the δ-selective (naltrindole, 3 mg/kg) or the κ-selective antagonist (norbinaltorphimine, 10 mg/kg) did not. In four macaques, PET imaging and kinetic modeling enabled description of the regional brain kinetics of 11 Cbuprenorphine, co-injected with increasing doses of unlabeled buprenorphine. No saturation of the brain penetration of buprenorphine was observed for doses up to 0.11 mg/kg. Regional differences in buprenorphine-associated receptor occupancy were observed. Analgesic doses of buprenorphine (0.003 and 0.006 mg/kg) respectively occupied 20% and 49% of receptors in the thalamus while saturating the low but significant binding observed in cerebellum and occipital cortex. Occupancy >90% was achieved in most brain regions with plasma concentrations >7 µg/L. PET data obtained after co-injection of an analgesic dose of buprenorphine (0.003 mg/kg) predicted the binding potential of microdose 11 Cbuprenorphine. This strategy could be further combined with pharmacodynamic exploration or pharmacological MRI to investigate the neuropharmacokinetics and neuroreceptor correlate, at least at µ-OR, of the acute effects of buprenorphine in humans.

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Section: Arterial Input Function and Metabolismmentioning

confidence: 99%

Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo

Auvity

Goutal

Caillé

et al. 2021

Neuropsychopharmacol.

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“…Additional plasma samples were obtained at 0, 5, 10, 15, 30, 60, and 90 min to measure the percentage of parent (unmetabolized) radiotracer using radio-HPLC and state of-the-art methodology. 31 The fraction of parent radiotracer in each sample was used to generate the metabolite-corrected arterial input function.…”

Section: Methodsmentioning

confidence: 99%

Brain PET imaging using ¹¹C-flumazenil and ¹¹C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level

Auvity,

Vodovar,

Goutal

et al. 2023

J Cereb Blood Flow Metab

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Among opioids, buprenorphine presents a favorable safety profile with a limited risk of respiratory depression. However, fatalities have been reported when buprenorphine is combined to a benzodiazepine. Potentiation of buprenorphine interaction with opioid receptors (ORs) with benzodiazepines, and/or vice versa, is hypothesized to explain this drug-drug interaction (DDI). The mutual DDI between buprenorphine and benzodiazepines was investigated at the neuroreceptor level in nonhuman primates (n = 4 individuals) using brain PET imaging and kinetic modelling. The binding potential (BPND) of benzodiazepine receptor (BzR) was assessed using 11C-flumazenil PET imaging before and after administration of buprenorphine (0.2 mg, i.v.). Moreover, the brain kinetics and receptor binding of buprenorphine were investigated in the same individuals using 11C-buprenorphine PET imaging before and after administration of diazepam (10 mg, i.v.). Outcome parameters were compared using a two-way ANOVA. Buprenorphine did not impact the plasma nor brain kinetics of 11C-flumazenil. 11C-flumazenil BPND was unchanged following buprenorphine exposure, in any brain region (p > 0.05). Similarly, diazepam did not impact the plasma or brain kinetics of 11C-buprenorphine. 11C-buprenorphine volume of distribution ( VT) was unchanged following diazepam exposure, in any brain region (p > 0.05). To conclude, our PET imaging findings do not support a neuropharmacokinetic or neuroreceptor-related mechanism of the buprenorphine/benzodiazepine interaction.

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“…Various approaches have been developed over the last decades to obtain the AIF in small animal models [6]: image-derived input function (IDIF) [7,8], machine learning derived AIF [9], population mean [10], intravascular β probe [11,12] and external blood radioactivity counters connected to an artery via a catheter [13][14][15][16][17][18][19]. The latter approach can provide a continuous input function independently of the imaged organ.…”

Section: Introductionmentioning

confidence: 99%

The ultra high sensitivity blood counter: a compact, MRI-compatible, radioactivity counter for pharmacokinetic studies in μl volumes

Convert

Sarrhini²,

Paillé³

et al. 2022

Biomed. Phys. Eng. Express

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Quantification of physiological parameters in preclinical pharmacokinetic studies based on nuclear imaging requires the monitoring of arterial radioactivity over time, known as the arterial input function (AIF). Continuous derivation of the AIF in rodent models is very challenging because of the limited blood volume available for sampling. To address this challenge, an Ultra High Sensitivity Blood Counter (UHS-BC) was developed. The device detects beta particles in real-time using silicon photodiodes, custom low-noise electronics, and 3D-printed plastic cartridges to hold standard catheters. Two prototypes were built and characterized in two facilities. Sensitivities up to 39% for 18F and 58% for 11C-based positron emission tomography (PET) tracers were demonstrated. 99mTc and 125I based Single Photon Emission Computed Tomography (SPECT) tracers were detected with greater than 3% and 10% sensitivity, respectively, opening new applications in nuclear imaging and fundamental biology research. Measured energy spectra show all relevant peaks down to a minimum detectable energy of 20 keV. The UHS-BC was shown to be highly reliable, robust towards parasitic background radiation and electromagnetic interference in the PET or MRI environment. The UHS-BC provides reproducible results under various experimental conditions and was demonstrated to be stable over days of continuous operation. Animal experiments showed that the UHS-BC performs accurate AIF measurements using low detection volumes suitable for small animal models in PET, SPECT and PET/MRI investigations. This tool will help to reduce the time and number of animals required for pharmacokinetic studies, thus increasing the throughput of new drug development.

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Determination of the Input Function at the Entry of the Tissue of Interest and Its Impact on PET Kinetic Modeling Parameters

Cited by 7 publications

References 71 publications

Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo

Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo

Brain PET imaging using ¹¹C-flumazenil and ¹¹C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level

The ultra high sensitivity blood counter: a compact, MRI-compatible, radioactivity counter for pharmacokinetic studies in μl volumes

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Determination of the Input Function at the Entry of the Tissue of Interest and Its Impact on PET Kinetic Modeling Parameters

Cited by 7 publications

References 71 publications

Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo

Pharmacokinetic neuroimaging to study the dose-related brain kinetics and target engagement of buprenorphine in vivo

Brain PET imaging using 11C-flumazenil and 11C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level

The ultra high sensitivity blood counter: a compact, MRI-compatible, radioactivity counter for pharmacokinetic studies in μl volumes

Contact Info

Product

Resources

About

Brain PET imaging using ¹¹C-flumazenil and ¹¹C-buprenorphine does not support the hypothesis of a mutual interaction between buprenorphine and benzodiazepines at the neuroreceptor level