UNLABELLED: 11C-Loperamide is an avid substrate for P-glycoprotein (P-gp), but it is rapidly metabolized to 11C-N-desmethyl-loperamide (11C-dLop), which is also a substrate for P-gp and thereby contaminates the radioactive signal in the brain. Should further demethylation of 11C-dLop occur, radiometabolites with low entry into the brain are generated. Therefore, we evaluated the ability of 11C-dLop to quantify the function of P-gp at the blood-brain barrier in monkeys. METHODS: Six monkeys underwent 12 PET scans of the brain, 5 at baseline and 7 after pharmacologic blockade of P-gp. A subset of monkeys also underwent PET scans with 15O-water to measure cerebral blood flow. To determine whether P-gp blockade affected peripheral distribution of 11C-dLop, we measured whole-body biodistribution in 4 monkeys at baseline and after P-gp blockade. RESULTS: The concentration of 11C-dLop in the brain was low under baseline conditions and increased 5-fold after P-gp blockade. This increase was primarily caused by an increased rate of entry into the brain rather than a decreased rate of removal from the brain. With P-gp blockade, uptake of radioactivity among brain regions correlated linearly with blood flow, suggesting a high single-pass extraction. After correction for cerebral blood flow, the uptake of 11C-dLop was fairly uniform among brain regions, suggesting that the function of P-gp is fairly uniformly distributed in the brain. On whole-body imaging, P-gp blockade significantly affected distribution of radioactivity only to the brain and not to other visually identified source organs. The effective dose estimated for humans was approximately 9 microSv/MBq. CONCLUSION: PET with 11C-dLop can quantify P-gp function at the blood-brain barrier in monkeys. The single-pass extraction of 11C-dLop is high and requires correction for blood flow to accurately measure the function of this efflux transporter. The low uptake at baseline and markedly increased uptake after P-gp blockade suggest that 11C-dLop will be useful to measure a wide range of P-gp functions at the blood-brain barrier in humans.
UNLABELLED: 11C-Loperamide is an avid substrate for P-glycoprotein (P-gp), but it is rapidly metabolized to 11C-N-desmethyl-loperamide (11C-dLop), which is also a substrate for P-gp and thereby contaminates the radioactive signal in the brain. Should further demethylation of 11C-dLop occur, radiometabolites with low entry into the brain are generated. Therefore, we evaluated the ability of 11C-dLop to quantify the function of P-gp at the blood-brain barrier in monkeys. METHODS: Six monkeys underwent 12 PET scans of the brain, 5 at baseline and 7 after pharmacologic blockade of P-gp. A subset of monkeys also underwent PET scans with 15O-water to measure cerebral blood flow. To determine whether P-gp blockade affected peripheral distribution of 11C-dLop, we measured whole-body biodistribution in 4 monkeys at baseline and after P-gp blockade. RESULTS: The concentration of 11C-dLop in the brain was low under baseline conditions and increased 5-fold after P-gp blockade. This increase was primarily caused by an increased rate of entry into the brain rather than a decreased rate of removal from the brain. With P-gp blockade, uptake of radioactivity among brain regions correlated linearly with blood flow, suggesting a high single-pass extraction. After correction for cerebral blood flow, the uptake of 11C-dLop was fairly uniform among brain regions, suggesting that the function of P-gp is fairly uniformly distributed in the brain. On whole-body imaging, P-gp blockade significantly affected distribution of radioactivity only to the brain and not to other visually identified source organs. The effective dose estimated for humans was approximately 9 microSv/MBq. CONCLUSION: PET with 11C-dLop can quantify P-gp function at the blood-brain barrier in monkeys. The single-pass extraction of 11C-dLop is high and requires correction for blood flow to accurately measure the function of this efflux transporter. The low uptake at baseline and markedly increased uptake after P-gp blockade suggest that 11C-dLop will be useful to measure a wide range of P-gp functions at the blood-brain barrier in humans.
Authors: Rudie Kortekaas; Klaus L Leenders; Joost C H van Oostrom; Willem Vaalburg; Joost Bart; Antoon T M Willemsen; N Harry Hendrikse Journal: Ann Neurol Date: 2005-02 Impact factor: 10.422
Authors: Neva Lazarova; Sami S Zoghbi; Jinsoo Hong; Nicholas Seneca; Ed Tuan; Robert L Gladding; Jeih-San Liow; Andrew Taku; Robert B Innis; Victor W Pike Journal: J Med Chem Date: 2008-09-11 Impact factor: 7.446
Authors: M Bauer; M Zeitlinger; R Karch; P Matzneller; J Stanek; W Jäger; M Böhmdorfer; W Wadsak; M Mitterhauser; J P Bankstahl; W Löscher; M Koepp; C Kuntner; M Müller; Oliver Langer Journal: Clin Pharmacol Ther Date: 2011-12-14 Impact factor: 6.875
Authors: Eduardo R Butelman; Michael Caspers; Kimberly M Lovell; Mary Jeanne Kreek; Thomas E Prisinzano Journal: J Pharmacol Exp Ther Date: 2012-03-20 Impact factor: 4.030
Authors: William C Kreisl; Jeih-San Liow; Nobuyo Kimura; Nicholas Seneca; Sami S Zoghbi; Cheryl L Morse; Peter Herscovitch; Victor W Pike; Robert B Innis Journal: J Nucl Med Date: 2010-03-17 Impact factor: 10.057
Authors: Martin Bauer; Rudolf Karch; Friederike Neumann; Claudia C Wagner; Kurt Kletter; Markus Müller; Wolfgang Löscher; Markus Zeitlinger; Oliver Langer Journal: J Cereb Blood Flow Metab Date: 2009-12-16 Impact factor: 6.200
Authors: Claudia Kuntner; Jens P Bankstahl; Marion Bankstahl; Johann Stanek; Thomas Wanek; Gloria Stundner; Rudolf Karch; Rebecca Brauner; Martin Meier; Xiaoqi Ding; Markus Müller; Wolfgang Löscher; Oliver Langer Journal: Eur J Nucl Med Mol Imaging Date: 2009-12-17 Impact factor: 9.236
Authors: Viktoria Zoufal; Thomas Wanek; Markus Krohn; Severin Mairinger; Thomas Filip; Michael Sauberer; Johann Stanek; Thomas Pekar; Martin Bauer; Jens Pahnke; Oliver Langer Journal: J Cereb Blood Flow Metab Date: 2018-10-24 Impact factor: 6.200