RT Journal Article
SR Electronic
T1 <sup>11</sup>C-Loperamide and Its <em>N</em>-<em>Desmethyl</em> Radiometabolite Are Avid Substrates for Brain Permeability-Glycoprotein Efflux
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 649
OP 656
DO 10.2967/jnumed.107.047308
VO 49
IS 4
A1 Sami S. Zoghbi
A1 Jeih-San Liow
A1 Fumihiko Yasuno
A1 Jinsoo Hong
A1 Edward Tuan
A1 Neva Lazarova
A1 Robert L. Gladding
A1 Victor W. Pike
A1 Robert B. Innis
YR 2008
UL http://jnm.snmjournals.org/content/49/4/649.abstract
AB Loperamide, an opiate receptor agonist, does not cross the blood–brain barrier because it is a substrate for the permeability-glycoprotein (P-gp) efflux pump. We evaluated 11C-loperamide as a PET radiotracer to measure P-gp function in vivo. Methods: Monkeys were injected with 11C-loperamide, and PET brain images were acquired for 120 min. The baseline scans were followed by scans acquired after administration of either of 2 P-gp inhibitors, (2R)-anti-5-{3-[4-(10,11-dichloromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (DCPQ) or tariquidar. Both the PET scans and ex vivo measurements were obtained in P-gp knockout and wild-type mice. Results: Pharmacologic inhibition of P-gp in monkeys dose-dependently increased brain activity, with a 3.7-fold effect at the highest DCPQ dose (8 mg/kg intravenously). This increase of brain activity was not caused peripherally, because DCPQ insignificantly changed the plasma concentration and plasma protein binding of radiotracer. Furthermore, the structurally dissimilar inhibitor, tariquidar, also increased brain uptake with potency equal to that of DCPQ. P-gp knockout mice had 3-fold higher brain activity on PET than did wild-type animals. Four radiometabolites were detected in the plasma and brains of ex vivo mice. The most lipophilic radiometabolite was found to be comobile with reference dLop on high-performance liquid chromatography. The brain concentrations of 11C-loperamide and the putative 11C-dLop were about 16-fold greater in P-gp knockout mice than in wild-type mice. Conclusion: Both 11C-loperamide and its putative radiometabolite 11C-dLop are avid P-gp substrates. 11C-dLop may be superior to 11C-loperamide in measuring P-gp function at the blood–brain barrier, because further demethylation of 11C-dLop will generate radiometabolites that have little entry into the brain.