RT Journal Article
SR Electronic
T1 P-Glycoprotein Function at the Blood–Brain Barrier Imaged Using <sup>11</sup>C-<em>N-Desmethyl</em>-Loperamide in Monkeys
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 108
OP 115
DO 10.2967/jnumed.108.056226
VO 50
IS 1
A1 Jeih-San Liow
A1 William Kreisl
A1 Sami S. Zoghbi
A1 Neva Lazarova
A1 Nicholas Seneca
A1 Robert L. Gladding
A1 Andrew Taku
A1 Peter Herscovitch
A1 Victor W. Pike
A1 Robert B. Innis
YR 2009
UL http://jnm.snmjournals.org/content/50/1/108.abstract
AB 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 μSv/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.