Effects of ketoconazole on the biodistribution and metabolism of [11C]loperamide and [11C]N-desmethyl-loperamide in wild-type and P-gp knockout mice.

Introduction: [(11)C]Loperamide and [(11)C]N-desmethyl-loperamide ([(11)C]dLop) have been proposed as radiotracers for imaging brain P-glycoprotein (P-gp) function. A major route of [(11)C]loperamide metabolism is N-demethylation to [(11)C]dLop. We aimed to test whether inhibition of CYP3A4 with ketoconazole might reduce the metabolism of [(11)C]loperamide and [(11)C]dLop in mice, and thereby improve the quality of these radiotracers.

N-desmethyl-loperamide is selective for P-glycoprotein among three ATP-binding cassette transporters at the blood-brain barrier.

[(11)C]N-desmethyl-Loperamide ([(11)C]dLop) is used in positron emission tomography (PET) to measure the in vivo activity of efflux transporters that block the passage of drugs across the blood-brain barrier. The three most prevalent ATP-binding cassette efflux transporters at the blood-brain barrier are P-glycoprotein (P-gp), multidrug resistance protein 1 (Mrp1), and breast cancer resistance protein (BCRP). We sought to measure the selectivity of dLop among these three transporters.

Quantification of translocator protein (18 kDa) in the human brain with PET and a novel radioligand, (18)F-PBR06.

Unlabelled: Translocator protein (TSPO) (18 kDa), formerly called the peripheral benzodiazepine receptor, is upregulated on activated microglia and macrophages and is, thus, a biomarker of inflammation. We previously reported that an (11)C-labeled aryloxyanilide (half-life, 20 min) was able to quantify TSPOs in the healthy human brain. Because many PET centers would benefit from a longer-lived (18)F-labeled radioligand (half-life, 110 min), the objective of this study was to evaluate the ability of a closely related aryloxyanilide ((18)F-N-fluoroacetyl-N-(2,5-dimethoxybenzyl)-2-phenoxyaniline [(18)F-PBR06]) to quantify TSPOs in the healthy human brain.

Human brain imaging and radiation dosimetry of 11C-N-desmethyl-loperamide, a PET radiotracer to measure the function of P-glycoprotein.

Unlabelled: 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 (11)C-dLop, compared with (11)C-loperamide, is an especially promising radiotracer because it generates negligible radiometabolites that enter the brain.

P-glycoprotein function at the blood-brain barrier imaged using 11C-N-desmethyl-loperamide in monkeys.

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.

Metabotropic glutamate subtype 5 receptors are quantified in the human brain with a novel radioligand for PET.

Unlabelled: We developed a radioligand, 3-fluoro-5-(2-(2-(18)F-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile ((18)F-SP203), for metabotropic glutamate subtype 5 (mGluR5) receptors that showed both promising (high specific binding) and problematic (defluorination) imaging characteristics in animals. The purposes of this initial evaluation in human subjects were to determine whether (18)F-SP203 is defluorinated in vivo (as measured by uptake of radioactivity in the skull) and to determine whether the uptake in the brain can be quantified as distribution volume relative to concentrations of (18)F-SP203 in plasma.

Methods: Seven healthy subjects were injected with (18)F-SP203 (323 +/- 87 MBq) and scanned over 5 h, with rest periods outside the camera.

Synthesis and evaluation of [N-methyl-11C]N-desmethyl-loperamide as a new and improved PET radiotracer for imaging P-gp function.

[(11)C]Loperamide has been proposed for imaging P-glycoprotein (P-gp) function with positron emission tomography (PET), but its metabolism to [N-methyl-(11)C] N-desmethyl-loperamide ([(11)C]dLop; [(11)C]3) precludes quantification. We considered that [(11)C]3 might itself be a superior radiotracer for imaging brain P-gp function and therefore aimed to prepare [(11)C]3 and characterize its efficacy. An amide precursor (2) was synthesized and methylated with [(11)C]iodomethane to give [(11)C]3.