Receptor imaging technique with 11C-labeled receptor ligands in living brain slices: its application to time-resolved imaging and saturation analysis of benzodiazepine receptor using [11C]Ro15-1788

Murata, Tetsuhito; Matsumura, Kiyoshi; Onoe, Hirotaka; Bergström, Mats; Takechi, Hajime; Sihver, Sven; Sihver, Wiebke; Neu, Henrik; Andersson, Yvonne; Ögren, Mattias; Fasth, Karl-Johan; Långström, Bengt; Watanabe, Yasuyoshi

doi:10.1016/0168-0102(96)01037-1

Cited by 28 publications

(14 citation statements)

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“…(27), and 54.5 ngÁmL 21 in rat brain homogenates (28). The K D estimate, 5.9 6 0.9 ngÁmL 21 , obtained in the present study is also in line with previously published studies (17,18,(25)(26)(27)(28). On the basis of time-activity data obtained in a previous study when 11 C-flumazenil was administered without the addition of unlabeled flumazenil (18), the doses used in the present study resulted in approximate occupancy levels of 30%-40% for 4-mg, 60%-70% for 20-mg, 70%-80% for 100-mg, and around 90% for 400-mg dose groups.…”

Section: Discussionsupporting

confidence: 82%

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET

et al. 2012

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The aim of the present study was to investigate if flumazenil blood-brain barrier transport and binding to the benzodiazepine site on the g-aminobutyric acid A (GABA A ) receptor complex is altered in an experimental model of epilepsy and subsequently to study if changes in P-glycoprotein (P-gp)-mediated efflux of flumazenil at the blood-brain barrier may confound interpretation of 11 C-flumazenil PET in epilepsy. Methods: The transport of flumazenil across the blood-brain barrier and the binding to the benzodiazepine site on the GABA A receptors in 5 different brain regions was studied and compared between controls and kainate-treated rats, a model of temporal lobe epilepsy, with and without tariquidar pretreatment. In total, 29 rats underwent 2 consecutive 11 C-flumazenil PET scans, each one lasting 30 min. The tracer was mixed with different amounts of isotopically unmodified flumazenil (4, 20, 100, or 400 mg) to cover a wide range of receptor occupancies during the scan. Before the second scan, the rats were pretreated with a 3 or 15 mg/kg dose of the P-gp inhibitor tariquidar. The second scan was then obtained according to the same protocol as the first scan. Results: GABA A receptor density, B max , was estimated as 44 6 2 ngÁmL 21 in the hippocampus and as 33 6 2 ngÁmL 21 in the cerebellum, with intermediate values in the occipital cortex, parietal cortex, and caudate putamen. B max was decreased by 12% in kainate-treated rats, compared with controls. The radiotracer equilibrium dissociation constant, K D , was similar in both rat groups and all brain regions and was estimated as 5.9 6 0.9 ngÁmL 21 . There was no difference in flumazenil transport across the blood-brain barrier between control and kainate-treated rats, and the effect of tariquidar treatment was similar in both rat groups. Tariquidar treatment also decreased flumazenil transport out of the brain by 73%, increased the volume of distribution in the brain by 24%, and did not influence B max or K D , compared with baseline . Conclusion: B max was decreased in kainate-treated rats, compared with controls, but no alteration in the bloodbrain barrier transport of flumazenil was observed. P-gp inhibition by tariquidar treatment increased brain concentrations of flumazenil in both groups, but B max estimates were not influenced, suggesting that 11 C-flumazenil scanning is not confounded by alterations in P-gp function.

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Section: Discussionsupporting

confidence: 82%

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET

et al. 2012

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“…The estimated in vivo K D (4.68 ng/ml) closely resembles reported in vitro K D values at 37-C of 2.2 ng/ml in living rat cortex slices [31], 3.2 ng/ml in rat cortex homogenates [32], and 7.1 ng/ml in rat brain homogenates [33]. Comparison of presently estimated B max with reported in vitro B max values is more difficult, because the latter values are usually expressed as mol per mg protein.…”

Section: Discussionsupporting

confidence: 76%

“…Comparison of presently estimated B max with reported in vitro B max values is more difficult, because the latter values are usually expressed as mol per mg protein. To overcome this, Murata et al assumed that 1 ml of brain tissue contains 100 mg protein [31]. Using this assumption, the presently estimated in vivo B max (14.5 ng/ml) is in the same order of magnitude as in vitro B max values of 4.4 ng/ml in living rat cortex slices [31], 3.3 ng/ml in rat cortex homogenates [32], and 6.…”

Section: Discussionmentioning

confidence: 94%

Population Pharmacokinetic Analysis for Simultaneous Determination of B max and K D In Vivo by Positron Emission Tomography

et al. 2005

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“…The ratio of [ 11 C]carvedilol uptake in the right over the left hemisphere was calculated. Exposition in each area was quantified with the aid of a calibration line, converted into Bq, and corrected for injected dose of [ 11 C]carvedilol and body mass (Murata et al, 1996;Sihver et al, 1997;Ishiwata et al, 1999).…”

Section: Uptake Of [ 11 C]carvedilol In the Brainmentioning

confidence: 99%

Irradiation of rat brain reduces P-glycoprotein expression and function

et al. 2007

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The blood -brain barrier (BBB) hampers delivery of several drugs including chemotherapeutics to the brain. The drug efflux pump P-glycoprotein (P-gp), expressed on brain capillary endothelial cells, is part of the BBB. P-gp expression on capillary endothelium decreases 5 days after brain irradiation, which may reduce P-gp function and increase brain levels of P-gp substrates. To elucidate whether radiation therapy reduces P-gp expression and function in the brain, right hemispheres of rats were irradiated with single doses of 2 -25 Gy followed by 10 mg kg À1 of the P-gp substrate cyclosporine A (CsA) intravenously (i.v.), with once 15 Gy followed by CsA (10, 15 or 20 mg kg À1 ), or with fractionated irradiation (4 Â 5 Gy) followed by CsA (10 mg kg À1 ) 5 days later. Additionally, four groups of three rats received 25 Gy once and were killed 10, 15, 20 or 25 days later. The brains were removed and P-gp detected immunohistochemically. P-gp function was assessed by [ 11 C]carvedilol uptake using quantitative autoradiography. Irradiation increased [11 C]carvedilol uptake dose-dependently, to a maximum of 20% above non irradiated hemisphere. CsA increased [ 11 C]carvedilol uptake dose-dependently in both hemispheres, but more (Po0.001) in the irradiated hemisphere. Fractionated irradiation resulted in a lost P-gp expression 10 days after start irradiation, which coincided with increased [ 11 C]carvedilol uptake. P-gp expression decreased between day 15 and 20 after single dose irradiation, and increased again thereafter. Rat brain irradiation results in a temporary decreased P-gp function.

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Receptor imaging technique with 11C-labeled receptor ligands in living brain slices: its application to time-resolved imaging and saturation analysis of benzodiazepine receptor using [11C]Ro15-1788

Cited by 28 publications

References 20 publications

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET

Population Pharmacokinetic Analysis for Simultaneous Determination of B max and K D In Vivo by Positron Emission Tomography

Irradiation of rat brain reduces P-glycoprotein expression and function

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Receptor imaging technique with 11C-labeled receptor ligands in living brain slices: its application to time-resolved imaging and saturation analysis of benzodiazepine receptor using [11C]Ro15-1788

Cited by 28 publications

References 20 publications

Altered GABAA Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using 11C-Flumazenil and PET

Altered GABAA Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using 11C-Flumazenil and PET

Population Pharmacokinetic Analysis for Simultaneous Determination of B max and K D In Vivo by Positron Emission Tomography

Irradiation of rat brain reduces P-glycoprotein expression and function

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Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET

Altered GABA_A Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using ¹¹C-Flumazenil and PET