Quantification of Dynamic <sup>11</sup>C-Phenytoin PET Studies

Mansor, Syahir; Boellaard, Ronald; Froklage, Femke E.; Bakker, Els D.; Yaqub, Maqsood; Voskuyl, Rob A.; Schwarte, Lothar A.; Verbeek, Joost; Windhorst, Albert D.; Lammertsma, Adriaan A.

doi:10.2967/jnumed.115.158055

Cited by 18 publications

(22 citation statements)

References 27 publications

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“…Transport of the antiepileptic drug phenytoin by the human P-gp was shown to be extremely weak compared with the rodent isoform (23,24) and is hardly detected using a bidirectional transport assay (16). 11 C-phenytoin PET is nonetheless an elegant strategy to study antiepileptic drug disposition in the brains of patients with pharmacoresistant epilepsy, which may involve parameters other than P-gp at the BBB (25,26).…”

Section: Discussionmentioning

confidence: 99%

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Pottier¹,

Marie²,

Goutal³

et al. 2015

J Nucl Med

105

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The effects of metoclopramide on the central nervous system (CNS) in patients suggest substantial brain distribution. Previous data suggest that metoclopramide brain kinetics may nonetheless be controlled by ATP-binding cassette (ABC) transporters expressed at the blood-brain barrier. We used 11 C-metoclopramide PET imaging to elucidate the kinetic impact of transporter function on metoclopramide exposure to the brain. Methods: 11 C-metoclopramide transport by P-glycoprotein (P-gp; ABCB1) and the breast cancer resistance protein (BCRP; ABCG2) was tested using uptake assays in cells overexpressing P-gp and BCRP. 11 C-metoclopramide brain kinetics were compared using PET in rats (n 5 4-5) in the absence and presence of a pharmacologic dose of metoclopramide (3 mg/kg), with or without P-gp inhibition using intravenous tariquidar (8 mg/kg). The 11 C-metoclopramide brain distribution (V T based on Logan plot analysis) and brain kinetics (2-tissue-compartment model) were characterized with either a measured or an imaged-derived input function. Plasma and brain radiometabolites were studied using radio-high-performance liquid chromatography analysis. Results: 11 C-metoclopramide transport was selective for P-gp over BCRP. Pharmacologic dose did not affect baseline 11 C-metoclopramide brain kinetics (V T 5 2.28 ± 0.32 and 2.04 ± 0.19 mL⋅cm −3 using microdose and pharmacologic dose, respectively). Tariquidar significantly enhanced microdose 11 C-metoclopramide V T (7.80 ± 1.43 mL⋅cm −3 ) with a 4.4-fold increase in K 1 (influx rate constant) and a 2.3-fold increase in binding potential (k 3 /k 4 ) in the 2-tissue-compartment model. In the pharmacologic situation, P-gp inhibition significantly increased metoclopramide brain distribution (V T 5 6.28 ± 0.48 mL⋅cm −3 ) with a 2.0-fold increase in K 1 and a 2.2-fold decrease in k 2 (efflux rate), with no significant impact on binding potential. In this situation, only parent 11 C-metoclopramide could be detected in the brains of P-gp-inhibited rats. Conclusion: 11 C-metoclopramide benefits from favorable pharmacokinetic properties that offer reliable quantification of P-gp function at the blood-brain barrier in a pharmacologic situation. Using metoclopramide as a model of CNS drug, we demonstrated that P-gp function not only reduces influx but also mediates the efflux from the brain back to the blood compartment, with additional impact on brain distribution. This PET-based strategy of P-gp function investigation may provide new insight on the contribution of P-gp to the variability of response to CNS drugs between patients.

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Section: Discussionmentioning

confidence: 99%

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Pottier¹,

Marie²,

Goutal³

et al. 2015

J Nucl Med

105

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“…In fact, prior studies using 18 F-FCWAY found decreased uptake in the temporal lobe of patients with drug-resistant epilepsy (Theodore et al, 2007), which may have been caused in part by increased expression of P-gp. As a further example, Mansor and colleagues recently reported the synthesis of 11 C-phenytoin, an anti-epileptic drug that often leads to resistance (Mansor et al, 2015). Although phenytoin is a substrate for both P-gp and BCRP, its brain uptake would surely be a direct measure of resistance at least to this medication and perhaps others that are associated with drug resistance (Nakanishi et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

18F-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier

Liow

Zoghbi

et al. 2016

NeuroImage

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Efflux transporters at the blood-brain barrier can decrease the entry of drugs and increase the removal of those molecules able to bypass the transporter. We previously hypothesized that 18F-FCWAY, a radioligand for the serotonin 5-HT1A receptor, is a weak substrate for permeability glycoprotein (P-gp) based on its very early peak and rapid washout from human brain. To determine whether 18F-FCWAY is a substrate for P-gp, breast cancer resistance protein (BCRP) and multidrug resistance protein (MRP1) — the three most prevalent efflux transporters at the blood-brain barrier — we performed three sets of experiments. In vitro, we conducted fluorescence-activated cell sorting (FACS) flow cytometry studies in cells over-expressing P-gp, BCRP and MRP1 treated with inhibitors specific to each transporter and with FCWAY. Ex vivo, we measured 18F-FCWAY concentration in plasma and brain homogenate of transporter knockout mice using γ-counter and radio-HPLC. In vivo, we conducted positron emission tomography (PET) studies to assess changes in humans who received 18F-FCWAY during an infusion of tariquidar (2 – 4 mg/kg iv), a potent and selective P-gp inhibitor. In vitro studies showed that FCWAY allowed fluorescent substrates to get into the cell by competitive inhibition of all three transporters at the cell membrane. Ex vivo measurements in knockout mice indicate that 18F-FCWAY is a substrate only for P-gp and not BCRP. In vivo, tariquidar increased 18F-FCWAY brain uptake in seven of eight subjects by 60–100% compared to each person’s baseline. Tariquidar did not increase brain uptake via some peripheral mechanism, given that it did not significantly alter concentrations in plasma of the parent radioligand 18F-FCWAY or its brain-penetrant radiometabolite 18F-FC. These results show that 18F-FCWAY is a weak substrate for efflux transport at the blood-brain barrier; some radioligand can enter brain, but its removal is hastened by P-gp. Although 18F-FCWAY is not ideal for measuring 5-HT1A receptors, it demonstrates that weak substrate radioligands can be useful for measuring both increased and decreased function of efflux transporters, which is not possible with currently available radioligands such as 11C-loperamide and 11C-verapamil that are avid substrates for transporters.

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“…The AIC fraction was also calculated by measuring the frequency of AIC preferences for each model across all subjects (17). AIC was calculated for the following brain regions: frontal, temporal, parietal, and occipital lobes; whole brain; posterior cingulate; thalamus; striatum; brain stem; medial temporal lobe; hippocampus; and cerebellum.…”

Section: Kinetic Modelingmentioning

confidence: 99%

Flutriciclamide (¹⁸F-GE180) PET: First-in-Human PET Study of Novel Third-Generation In Vivo Marker of Human Translocator Protein

et al. 2016

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Neuroinflammation is associated with neurodegenerative disease. PET radioligands targeting the 18-kDa translocator protein (TSPO) have been used as in vivo markers of neuroinflammation, but there is an urgent need for novel probes with improved signal-to-noise ratio. Flutriciclamide ( 18 F-GE180) is a recently developed thirdgeneration TSPO ligand. In this first study, we evaluated the optimum scan duration and kinetic modeling strategies for 18 F-GE180 PET in (older) healthy controls. Methods: Ten healthy controls, 6 TSPO high-affinity binders, and 4 mixed-affinity binders were recruited. All subjects underwent detailed neuropsychologic tests, MRI, and a 210-min 18 F-GE180 dynamic PET/CT scan using metabolite-corrected arterial plasma input function. We evaluated 5 different kinetic models: irreversible and reversible 2-tissue-compartment models, a reversible 1-tissue model, and 2 models with an extra irreversible vascular compartment. The minimal scan duration was established using 210-min scan data. The feasibility of generating parametric maps was also investigated using graphical analysis. Results: 18 F-GE180 concentration was higher in plasma than in whole blood during the entire scan duration. The volume of distribution (V T ) was 0.17 in high-affinity binders and 0.12 in mixed-affinity binders using the kinetic model. The model that best represented brain 18 F-GE180 kinetics across regions was the reversible 2-tissue-compartment model (2TCM4k), and 90 min resulted as the optimum scan length required to obtain stable estimates. Logan graphical analysis with arterial input function gave a V T highly consistent with V T in the kinetic model, which could be used for voxelwise analysis. Conclusion: We report for the first time, to our knowledge, the kinetic properties of the novel third-generation TSPO PET ligand 18 F-GE180 in humans: 2TCM4k is the optimal method to quantify the brain uptake, 90 min is the optimal scan length, and the Logan approach could be used to generate parametric maps. Although these control subjects have shown relatively low V T , the methodology presented here forms the basis for quantification for future PET studies using 18 F-GE180 in different pathologies.

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Quantification of Dynamic ¹¹C-Phenytoin PET Studies

Cited by 18 publications

References 27 publications

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

18F-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier

Flutriciclamide (¹⁸F-GE180) PET: First-in-Human PET Study of Novel Third-Generation In Vivo Marker of Human Translocator Protein

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Quantification of Dynamic 11C-Phenytoin PET Studies

Cited by 18 publications

References 27 publications

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

Imaging the Impact of the P-Glycoprotein (ABCB1) Function on the Brain Kinetics of Metoclopramide

18F-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier

Flutriciclamide (18F-GE180) PET: First-in-Human PET Study of Novel Third-Generation In Vivo Marker of Human Translocator Protein

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Quantification of Dynamic ¹¹C-Phenytoin PET Studies

Flutriciclamide (¹⁸F-GE180) PET: First-in-Human PET Study of Novel Third-Generation In Vivo Marker of Human Translocator Protein