Human Brain Imaging and Radiation Dosimetry of 11C-N-Desmethyl-Loperamide, a PET Radiotracer to Measure the Function of P-Glycoprotein
Open Access
- 16 April 2009
- journal article
- Published by Society of Nuclear Medicine in Journal of Nuclear Medicine
- Vol. 50 (5), 807-813
- https://doi.org/10.2967/jnumed.108.058453
Abstract
P-glycoprotein (P-gp) is a membrane-bound efflux pump that limits the distribution of drugs to several organs of the body. At the blood–brain barrier, P-gp blocks the entry of both loperamide and its metabolite, N-desmethyl-loperamide (N-dLop), and thereby prevents central opiate effects. Animal studies have shown that 11C-dLop, compared with 11C-loperamide, is an especially promising radiotracer because it generates negligible radiometabolites that enter the brain. The purposes of this study were to determine whether 11C-dLop is a substrate for P-gp at the blood–brain barrier in humans and to measure the distribution of radioactivity in the entire body to estimate radiation exposure. Methods: Brain PET scans were acquired in 4 healthy subjects for 90 min and included concurrent measurements of the plasma concentration of unchanged radiotracer. Time–activity data from the whole brain were quantified using a 1-tissue-compartment model to estimate the rate of entry (K1) of radiotracer into the brain. Whole-body PET scans were acquired in 8 healthy subjects for 120 min. Results: For brain imaging, after the injection of 11C-dLop the concentration of radioactivity in the brain was low (standardized uptake value, ∼15%) and stable after approximately 20 min. In contrast, uptake of radioactivity in the pituitary was about 50-fold higher than that in the brain. The plasma concentration of 11C-dLop declined rapidly, but the percentage composition of plasma was unusually stable, with the parent radiotracer constituting 85% of total radioactivity after approximately 5 min. The rate of brain entry was low (K1 = 0.009 ± 0.002 mL·cm−3·min−1; n = 4). For whole-body imaging, as a measure of radiation exposure to the entire body the effective dose of 11C-dLop was 7.8 ± 0.6 μSv/MBq (n = 8). Conclusion: The low brain uptake of radioactivity is consistent with 11C-dLop being a substrate for P-gp in humans and confirms that this radiotracer generates negligible quantities of brain-penetrant radiometabolites. In addition, the low rate of K1 is consistent with P-gp rapidly effluxing substrates while they transit through the lipid bilayer. The radiation exposure of 11C-dLop is similar to that of many other 11C-radiotracers. Thus, 11C-dLop is a promising radiotracer to study the function of P-gp at the blood–brain barrier, at which impaired function would allow increased uptake into the brain.Keywords
This publication has 18 references indexed in Scilit:
- The role of P-glycoprotein on blood brain barrier permeability of [11C]Loperamide in humansNeuroImage, 2008
- P-Glycoprotein Function at the Blood–Brain Barrier Imaged Using 11C-N-Desmethyl-Loperamide in MonkeysJournal of Nuclear Medicine, 2008
- Synthesis and Evaluation of [N-methyl-11C]N-Desmethyl-loperamide as a New and Improved PET Radiotracer for Imaging P-gp FunctionJournal of Medicinal Chemistry, 2008
- Whole-body biodistribution and radiation dosimetry in monkeys and humans of the phosphodiesterase 4 radioligand [11C](R)-rolipram: comparison of two-dimensional planar, bisected and quadrisected image analysesNuclear Medicine and Biology, 2008
- Radiation Dosimetry and Biodistribution in Monkey and Man of 11C-PBR28: A PET Radioligand to Image InflammationJournal of Nuclear Medicine, 2007
- Evaluation of Tracer Kinetic Models for Quantification of P-Glycoprotein Function using (R)-[11C]Verapamil and PETJournal of Cerebral Blood Flow & Metabolism, 2006
- In Vivo Evaluation of P-glycoprotein Function at the Blood-Brain Barrier in Nonhuman Primates Using [11C]VerapamilJournal of Pharmacology and Experimental Therapeutics, 2005
- Evaluation of (R)-[11C]verapamil as PET tracer of P-glycoprotein function in the blood–brain barrier: kinetics and metabolism in the ratNuclear Medicine and Biology, 2005
- Importance of P-glycoprotein at blood–tissue barriersTrends in Pharmacological Sciences, 2004
- Evaluation of Ultrafiltration for the Free‐Fraction Determination of Single Photon Emission Computed Tomography (SPECT) Radiotracers: β‐CIT, IBF, and IomazenilJournal of Pharmaceutical Sciences, 1994