Head-to-head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

García-Varela, Lara; García, David Vállez; Aguiar, Pablo; Kakiuchi, Takeharu; Ohba, Hideki; Harada, Norihiro; Nishiyama, Shingo; Tago, Tetsuro; Elsinga, Philip H.; Tsukada, Hideo; Colabufo, Nicola Antonio; Dierckx, Rudi; Waarde, Aren van; Toyohara, Jun; Boellaard, Ronald; Luurtsema, Gert

doi:10.1007/s00259-021-05411-2

Cited by 8 publications

(7 citation statements)

References 49 publications

(57 reference statements)

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“…Specifically, it has been demonstrated to be transported selectively by P-gp, but not BCRP, another important ABC transporter at the BBB. 66,67 Savolainen et al 68 measured the distribution of [ 18 F]MC225 by positron emission tomography in rat brains at 4 different time points. At ZT15, the distribution was 1.2 to 1.8× higher than at other time points suggesting that [ 18 F]MC225 efflux is reduced at the beginning of the active phase.…”

Section: Compendium: Circadian Mechanisms In Cardio/ Cerebrovascular ...mentioning

confidence: 99%

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

Kim,

Keep,

Zhang

2024

Circulation Research

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The blood-brain barrier (BBB) is a critical interface separating the central nervous system from the peripheral circulation, ensuring brain homeostasis and function. Recent research has unveiled a profound connection between the BBB and circadian rhythms, the endogenous oscillations synchronizing biological processes with the 24-hour light-dark cycle. This review explores the significance of circadian rhythms in the context of BBB functions, with an emphasis on substrate passage through the BBB. Our discussion includes efflux transporters and the molecular timing mechanisms that regulate their activities. A significant focus of this review is the potential implications of chronotherapy, leveraging our knowledge of circadian rhythms for improving drug delivery to the brain. Understanding the temporal changes in BBB can lead to optimized timing of drug administration, to enhance therapeutic efficacy for neurological disorders while reducing side effects. By elucidating the interplay between circadian rhythms and drug transport across the BBB, this review offers insights into innovative therapeutic interventions.

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Section: Compendium: Circadian Mechanisms In Cardio/ Cerebrovascular ...mentioning

confidence: 99%

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

Kim,

Keep,

Zhang

2024

Circulation Research

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“…Intestinal P-gp is located in the apical membrane of its epithelial cells and is recognized as a major factor affecting the kinetics of drugs that are taken orally. The increase in P-gp function is associated with the decrease in drug efficiency (drug resistance) [45]. Inhibition of P-gp can effectively prevent the drug pump effect of P-gp, reduce drug efflux and improve drug bioavailability in vivo.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Effects of Ginsenoside Rb3 and Ferruginol in Ischemia-Induced Myocardial Infarction

Chen

Liu

Wang

et al. 2022

IJMS

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Previous research shows that ginsenoside Rb3 (G-Rb3) exhibit significant protective effects on cardiomyocytes and is considered a promising treatment for myocardial infraction (MI). However, how to improve its oral bioavailability and reduce its dosage remains to be studied. Previous studies suggest that Ferruginol (FGL) may have synergistic effects with G-Rb3. However, the underlying mechanisms remain to be explored. In this study, left anterior descending branch (LAD) coronary artery ligation or oxygen-glucose deprivation-reperfusion (OGD/R) were used to establish MI models in vivo and in vitro. Subsequently, the pharmacological effects and mechanisms of G-Rb3-FGL were explored by in vitro studies. The results showed that the G-Rb3-FGL co-treatment improved heart functions better than the G-Rb3 treatment alone in MI mice models. Meanwhile, the G-Rb3-FGL co-treatment can upregulate fatty acids oxidation (FAO) and suppress oxidative stress in the heart tissues of MI mice. In vitro studies demonstrated that the synergistic effect of G-Rb3-FGL on FAO, oxidation and inflammation was abolished by RXRα inhibitor HX531 in the H9C2 cell model. In summary, we revealed that G-Rb3 and FGL have a synergistic effect against MI. They protected cardiomyocytes by promoting FAO, inhibiting oxidative stress, and suppressing inflammation through the RXRα-Nrf2 signaling pathway.

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“…However, one of the major drawbacks of (R) -[ 11 C]verapamil is the fact that is a so-called avid or strong substrate. This means that its brain uptake in a normal or healthy P-gp state is very low and therefore reliable quantification is very challenging [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Quantification of P-glycoprotein function at the human blood-brain barrier using [18F]MC225 and PET

Mossel

Arif

Souza

et al. 2023

Eur J Nucl Med Mol Imaging

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Introduction P-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer’s disease and Parkinson’s disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[11C]verapamil PET. (R)-[11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [18F]MC225 was developed to measure both increases and decreases in P-gp function. Aim The aim of this study was (1) to identify the pharmacokinetic model that best describes [18F]MC225 kinetics in the human brain and (2) to determine test-retest variability. Methods Five (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (VT), Ki, and the rate constants K1 and k2). In addition, a reversible two-tissue compartment model with fixed k3/k4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility. Results Sixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (VB) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the VT for [18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model. Conclusion [18F]MC225 VT, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%. Trial registration EudraCT 2020-001564-28. Registered 25 May 2020.

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Head-to-head comparison of (R)-[11C]verapamil and [18F]MC225 in non-human primates, tracers for measuring P-glycoprotein function

Cited by 8 publications

References 49 publications

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

Synergistic Effects of Ginsenoside Rb3 and Ferruginol in Ischemia-Induced Myocardial Infarction

Quantification of P-glycoprotein function at the human blood-brain barrier using [18F]MC225 and PET

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