Evaluation of P-glycoprotein function at the blood–brain barrier using [18F]MC225-PET

Mossel, Pascalle; Varela, Lara García; Arif, Wejdan M.; Weijden, Chris W.J. van der; Boersma, Hendrikus H.; Willemsen, Antoon T. M.; Boellaard, Ronald; Elsinga, Philip H.; Borra, Ronald; Colabufo, Nicola Antonio; Toyohara, Jun; Deyn, Peter Paul De; Dierckx, Rudi; Lammertsma, Adriaan A.; Bartels, Anna L.; Luurtsema, Gert

doi:10.1007/s00259-021-05419-8

Cited by 10 publications

(9 citation statements)

References 4 publications

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“…[ 11 C]metoclopramide and [ 18 F]MC225). [28][29][30][31][32] It is not known, however, whether such radiotracers display an adequate sensitivity to detect moderate, physiologically relevant changes in cerebral P-gp function.…”

Section: Introductionmentioning

confidence: 99%

[¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

Mairinger,

Leterrier,

Filip

et al. 2023

J Cereb Blood Flow Metab

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The efflux transporter P-glycoprotein (P-gp) at the blood-brain barrier limits the cerebral uptake of various xenobiotics. To assess the sensitivity of [11C]metoclopramide to measure decreased cerebral P-gp function, we performed [11C]metoclopramide PET scans without (baseline) and with partial P-gp inhibition by tariquidar in wild-type, heterozygous Abcb1a/b(+/−) and homozygous Abcb1a/b(−/−) mice as models with controlled levels of cerebral P-gp expression. Brains were collected to quantify P-gp expression with immunohistochemistry. Brain uptake of [11C]metoclopramide was expressed as the area under the brain time-activity curve (AUCbrain) and compared with data previously obtained with ( R)-[11C]verapamil and [11C] N-desmethyl-loperamide. Abcb1a/b(+/−) mice had intermediate P-gp expression compared to wild-type and Abcb1a/b(−/−) mice. In baseline scans, all three radiotracers were able to discriminate Abcb1a/b(−/−) from wild-type mice (2.5- to 4.6-fold increased AUCbrain, p ≤ 0.0001). However, only [11C]metoclopramide could discriminate Abcb1a/b(+/−) from wild-type mice (1.46-fold increased AUCbrain, p ≤ 0.001). After partial P-gp inhibition, differences in [11C]metoclopramide AUCbrain between Abcb1a/b(+/−) and wild-type mice (1.39-fold, p ≤ 0.001) remained comparable to baseline. There was a negative correlation between baseline [11C]metoclopramide AUCbrain and ex-vivo-measured P-gp immunofluorescence (r = −0.9875, p ≤ 0.0001). Our data suggest that [11C]metoclopramide is a sensitive radiotracer to measure moderate, but (patho-)physiologically relevant decreases in cerebral P-gp function without the need to co-administer a P-gp inhibitor.

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Section: Introductionmentioning

confidence: 99%

[¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

Mairinger,

Leterrier,

Filip

et al. 2023

J Cereb Blood Flow Metab

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“…It is necessary in future studies to determine whether [ 18 F]MC225 can detect functional impact on disease-induced reduction or induction of P-gp at the BBB and to conduct further test-retest and drug-loading validation of [ 18 F]MC225. These validation studies are currently ongoing and preliminary impressive drug-loading images have been reported [59].…”

Section: Discussionmentioning

confidence: 95%

First clinical assessment of [18F]MC225, a novel fluorine-18 labelled PET tracer for measuring functional P-glycoprotein at the blood–brain barrier

et al. 2021

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Objective 5-(1-(2-[ 18 F]fluoroethoxy))- [3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8-tetrahydronaphthalen ([ 18 F]MC225) is a selective substrate for P-glycoprotein (P-gp), possessing suitable properties for measuring overexpression of P-gp in the brain. This is the first-in-human study to examine safety, radiation dosimetry and P-gp function at the blood-brain barrier (BBB) of [ 18 F]MC225 in healthy subjects. Methods [ 18 F]MC225 biodistribution and dosimetry were determined in 3 healthy male subjects, using serial 2 h and intermittent 4 and 6 h whole-body PET scans acquired after [ 18 F]MC225 injection. Dynamic [ 18 F]MC225 brain PET (90 min) was obtained in 5 healthy male subjects. Arterial blood was sampled at various time intervals during scanning and the fraction of unchanged [ 18 F]MC225 in plasma was determined. T1-weighted MRI was performed for anatomical coregistration. Total distribution volume (V T ) was estimated using 1-and 2-tissue-compartment models (1-TCM and 2-TCM, respectively). V T was also estimated using the Logan graphical method (Logan plot) (t* = 20 min). Surrogate parameters without blood sampling (area-under the curve [AUC] of regional time-activity curves [TACs] and negative slope of calculated TACs) were compared with the V T values. ResultsNo serious adverse events occurred throughout the study period. Although biodistribution implied hepatobiliary excretion, secretion of radioactivity from liver to small intestine through the gallbladder was very slow. Total renal excreted radioactivity recovered during 6 h after injection was < 2%ID. Absorbed dose was the highest in the pancreas (mean ± SD, 203 ± 45 μGy/MBq) followed by the liver (83 ± 11 μGy/MBq). Mean effective dose with and without urination was 17 ± 1 μSv/MBq. [ 18 F]MC225 readily entered the brain, distributing homogeneously in grey matter regions. 2-TCM provided lower Akaike information criterion scores than did 1-TCM. V T estimated by Logan plot was well correlated with that of 2-TCM (r 2 > 0.9). AUCs of TACs were positively correlated with V T (2-TCM) values (r 2 : AUC 0-60 min = 0.61, AUC 0-30 min = 0.62, AUC 30-60 min = 0.59, p < 0.0001). Negative slope of SUV TACs was negatively correlated with V T (2-TCM) values (r 2 = 0.53, p < 0.0001). Conclusions This initial evaluation indicated that [ 18 F]MC225 is a suitable and safe PET tracer for measuring P-gp function at the BBB.

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“…Several different radiolabeled P‐gp substrates have been described for assessing P‐gp activity at the human BBB. These include [ 11 C] N ‐desmethyl‐loperamide, racemic or ( R )‐[ 11 C]verapamil, [ 18 F]MC225 and [ 11 C]metoclopramide 17,21–24 . [ 11 C] N ‐desmethyl‐loperamide and ( R )‐[ 11 C]verapamil are very efficiently transported by P‐gp at the BBB, resulting in very low brain uptake when P‐gp is fully functional, and are therefore not ideal probe substrates to detect a P‐gp induction at the BBB with PET.…”

Section: Discussionmentioning

confidence: 99%

St. John's wort extract with a high hyperforin content does not induce P‐glycoprotein activity at the human blood–brain barrier

El Biali,

Wölfl‐Duchek,

Jackwerth

et al. 2024

Clinical Translational Sci

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St. John's wort (SJW) extract, a herbal medicine with antidepressant effects, is a potent inducer of intestinal and/or hepatic cytochrome P450 (CYP) enzymes and P‐glycoprotein (P‐gp), which can cause clinically relevant drug interactions. It is currently not known whether SJW can also induce P‐gp activity at the human blood–brain barrier (BBB), which may potentially lead to decreased brain exposure and efficacy of certain central nervous system (CNS)‐targeted P‐gp substrate drugs. In this study, we used a combination of positron emission tomography (PET) imaging and cocktail phenotyping to gain a comprehensive picture on the effect of SJW on central and peripheral P‐gp and CYP activities. Before and after treatment of healthy volunteers (n = 10) with SJW extract with a high hyperforin content (3–6%) for 12–19 days (1800 mg/day), the activity of P‐gp at the BBB was assessed by means of PET imaging with the P‐gp substrate [11C]metoclopramide and the activity of peripheral P‐gp and CYPs was assessed by administering a low‐dose phenotyping cocktail (caffeine, omeprazole, dextromethorphan, and midazolam or fexofenadine). SJW significantly increased peripheral P‐gp, CYP3A, and CYP2C19 activity. Conversely, no significant changes in the peripheral metabolism, brain distribution, and P‐gp‐mediated efflux of [11C]metoclopramide across the BBB were observed following the treatment with SJW extract. Our data suggest that SJW does not lead to significant P‐gp induction at the human BBB despite its ability to induce peripheral P‐gp and CYPs. Simultaneous intake of SJW with CNS‐targeted P‐gp substrate drugs is not expected to lead to P‐gp‐mediated drug interactions at the BBB.

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Evaluation of P-glycoprotein function at the blood–brain barrier using [18F]MC225-PET

Cited by 10 publications

References 4 publications

[¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

[¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

First clinical assessment of [18F]MC225, a novel fluorine-18 labelled PET tracer for measuring functional P-glycoprotein at the blood–brain barrier

St. John's wort extract with a high hyperforin content does not induce P‐glycoprotein activity at the human blood–brain barrier

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Evaluation of P-glycoprotein function at the blood–brain barrier using [18F]MC225-PET

Cited by 10 publications

References 4 publications

[11C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

[11C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

First clinical assessment of [18F]MC225, a novel fluorine-18 labelled PET tracer for measuring functional P-glycoprotein at the blood–brain barrier

St. John's wort extract with a high hyperforin content does not induce P‐glycoprotein activity at the human blood–brain barrier

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Product

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[¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier

[¹¹C]metoclopramide is a sensitive radiotracer to measure moderate decreases in P-glycoprotein function at the blood-brain barrier