Human Biodistribution and Radiation Dosimetry of the P-Glycoprotein Radiotracer [11C]Metoclopramide

Martin Bauer,Karsten Bamminger,Markus Zeitlinger,Konstantin Prosenz,Nicolas Tournier,Georgios Karanikas,Sandra Barna,Matthias Blaickner,Oliver Langer,Verena Pichler,Marcus Hacker

doi:10.1007/s11307-021-01582-4

Abstract

PurposeTo assess in healthy volunteers the whole-body distribution and dosimetry of [11C]metoclopramide, a new positron emission tomography (PET) tracer to measure P-glycoprotein activity at the blood-brain barrier.ProceduresTen healthy volunteers (five women, five men) were intravenously injected with 387 ± 49 MBq of [11C]metoclopramide after low dose CT scans and were then imaged by whole-body PET scans from head to upper thigh over approximately 70 min. Ten source organs (brain, thyroid gland, right lung, myocardium, liver, gall bladder, left kidney, red bone marrow, muscle and the contents of the urinary bladder) were manually delineated on whole-body images. Absorbed doses were calculated with QDOSE (ABX-CRO) using the integrated IDAC-Dose 2.1 module.ResultsThe majority of the administered dose of [11C]metoclopramide was taken up into the liver followed by urinary excretion and, to a smaller extent, biliary excretion of radioactivity. The mean effective dose of [11C]metoclopramide was 1.69 ± 0.26 μSv/MBq for female subjects and 1.55 ± 0.07 μSv/MBq for male subjects. The two organs receiving the highest radiation doses were the urinary bladder (10.81 ± 0.23 μGy/MBq and 8.78 ± 0.89 μGy/MBq) and the liver (6.80 ± 0.78 μGy/MBq and 4.91 ± 0.74 μGy/MBq) for female and male subjects, respectively.Conclusions[11C]Metoclopramide showed predominantly renal excretion, and is safe and well tolerated in healthy adults. The effective dose of [11C]metoclopramide was comparable to other 11C-labeled PET tracers.

Highlights

P-glycoprotein (P-gp, encoded by the ABCB1 gene) is a membrane transporter which accepts a variety of endogenous substances and drugs as its substrates [1]
The study protocol was approved by the Medical University of Vienna Institutional Ethics committee, registered under EudraCT 2017–000989-30 and written informed consent was obtained from all subjects before enrolment. 10 healthy volunteers were included into the study, 5 men and 5 women
When comparing the group in which the excreted urine measurement was considered in the dosimetry calculation and the group in which no urine was sampled after the Positron emission tomography (PET)/CT scan, absorbed urinary bladder wall doses were only slightly higher (11 %) for the former group and effective doses were similar for both groups (2 % difference)

Summary

Introduction

P-glycoprotein (P-gp, encoded by the ABCB1 gene) is a membrane transporter which accepts a variety of endogenous substances and drugs as its substrates [1]. Positron emission tomography (PET) with radiolabeled Pgp substrates, such as racemic [11C]verapamil [2, 3], (R)[11C]verapamil [4, 5] and [11C]N-desmethyl-loperamide [6], has been proposed as a useful tool to measure P-gp activity at the BBB in health and disease. These radiotracers are very efficiently transported by P-gp at the BBB (“avid” P-gp substrates) leading to very low brain uptake and limited sensitivity to measure disease-induced alterations in P-gp activity at the BBB [7]. These radiotracers are very efficiently transported by P-gp at the BBB (“avid” P-gp substrates) leading to very low brain uptake and limited sensitivity to measure disease-induced alterations in P-gp activity at the BBB [7]. [11C]Metoclopramide is a weak P-gp substrate, which shows higher baseline brain uptake than previously described “avid” P-gp substrates and may possess better sensitivity to measure P-gp activity at the BBB, in particular in conditions in which the activity of P-gp is upregulated (e.g. drug-resistant epilepsy) [8,9,10,11,12]

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