Examples of progress made during the prior year are summarized below. 1) We demonstrated that the function of permeability glycoprotein (P-gp) could be selectively measured using a combination of tariquidar (a P-gp inhibitor) and the radiotracer 11CN-desmethyl-loperamide (dLop) (Kannan et al 2011). The radiotracer 11CdLop images the in vivo function of P-gp, a transporter that blocks the entry of drugs that are substrates into brain. When P-gp is inhibited, 11CdLop, a potent opiate agonist, enters and becomes trapped in the brain. This trapping is beneficial from an imaging perspective, because it amplifies the PET signal, essentially by accumulating radioactivity over time. A previous study from our laboratory demonstrated that this trapping was not caused by binding to opiate receptors;thus, we examined whether 11CdLop, a weak base, is ionically trapped in acidic lysosomes. To test this hypothesis, we measured 3HdLop accumulation in human cells by using lysosomotropics. Because the in vivo trapping of dLop was seen after P-gp inhibition, we also measured 3HdLop uptake in P-gp-expressing cells treated with the P-gp inhibitor tariquidar. All lysosomotropics decreased 3HdLop accumulation by at least 50%. Surprisingly, we found that in P-gp-expressing cells, tariquidar (and another P-gp inhibitor) decreased 3HdLop uptake. Consequently, we measured 11CdLop uptake before and after pre-administration of tariquidar in lysosome-rich organs of P-gp knockout (KO) mice and humans. After tariquidar pre-treatment in both species, radioactivity uptake in these organs decreased by 35% to 40%. Our results indicate that dLop is trapped in lysosomes and that tariquidar competes with dLop for lysosomal accumulation in vitro and in vivo. Although tariquidar and dLop compete for lysosomal trapping in the periphery, such competition does not occur in brain because tariquidar has negligible entry into brain. In summary, tariquidar and 11CdLop can be used in combination to selectively measure the function of P-gp at the blood-brain barrier. 2) Our laboratory developed 11C-NOP-1A, a new radioligand for the nociceptin/orphanin FQ peptide (NOP) receptor. We found that 11C-NOP-1A is a useful radioligand for quantifying NOP receptors in monkey brain, and that its radiation dose is similar to that of other 11C-labeled ligands for neuroreceptors. Taken together, the results suggest that 11CNOP-1A is a promising candidate for measuring NOP receptors in human brain (Kimura et al, in press). 11C-NOP-1A, a new radioligand for the NOP receptor, has high affinity (Ki = 0.15 nM) and appropriate lipophilicity (measured logD = 3.4) for PET brain imaging. Our study assessed the utility of 11C-NOP-1A for quantifying NOP receptors in monkey brain and estimated the radiation safety profile of this radioligand based on its biodistribution in monkeys. Baseline and blocking PET scans were acquired from head to thigh on three rhesus monkeys for approximately 120 minutes after 11C-NOP-1A injection. These six PET scans were used to quantify NOP receptors in brain and to estimate radiation exposure to organs of the body. In the blocked scans, a selective nonradioactive NOP receptor antagonist (SB-612111;1 mg/kg i.v.) was administered before 11C-NOP-1A. In all scans, arterial blood was sampled to measure the parent radioligand 11C-NOP-1A. Distribution volume (VT;a measure of receptor density) was calculated with a compartment model using brain and arterial plasma data. Radiation-absorbed doses were calculated using the Medical Internal Radiation Dose Committee scheme. After 11C-NOP-1A injection, peak uptake of radioactivity in brain had a high concentration (5 SUV), occurred early (12 minutes), and thereafter washed out quickly. VT (mL E cm-3) was highest in neocortex (20) and lowest in hypothalamus and cerebellum (13). SB-612111 blocked 50-70% of uptake and reduced VT in all brain regions to 7 mL E cm-3. Distribution was well identified within 60 minutes of injection and stable for the remaining 60 minutes, consistent with only parent radioligand and not radiometabolites entering brain. Whole body scans confirmed that the brain had specific (i.e., displaceable) binding but could not detect specific binding in peripheral organs. The effective dose for humans estimated from the baseline scans in monkeys was 5.0 Sv/MBq. 11C-NOP-1A is a useful radioligand for quantifying NOP receptors in monkey brain, and its radiation dose is similar to that of other 11C-labeled ligands for neuroreceptors. Thus, 11CNOP- 1A appears to be a promising candidate for measuring NOP receptors in human brain.

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Brouwer, Chad; Jenko, Kimberly J; Zoghbi, Sami S et al. (2016) Translocator protein ligands based on N-methyl-(quinolin-4-yl)oxypropanamides with properties suitable for PET radioligand development. Eur J Med Chem 124:677-688
Weidner, Lora D; Fung, King Leung; Kannan, Pavitra et al. (2016) Tariquidar Is an Inhibitor and Not a Substrate of Human and Mouse P-glycoprotein. Drug Metab Dispos 44:275-82
Liow, Jeih-San; Zoghbi, Sami S; Hu, Shuo et al. (2016) (18)F-FCWAY, a serotonin 1A receptor radioligand, is a substrate for efflux transport at the human blood-brain barrier. Neuroimage 138:134-140
Naumiec, Gregory R; Jenko, Kimberley J; Zoghbi, Sami S et al. (2015) N'-3-(Trifluoromethyl)phenyl Derivatives of N-Aryl-N'-methylguanidines as Prospective PET Radioligands for the Open Channel of the N-Methyl-d-aspartate (NMDA) Receptor: Synthesis and Structure-Affinity Relationships. J Med Chem 58:9722-30
Hong, Jinsoo; Lu, Shuiyu; Xu, Rong et al. (2015) [carbonyl-11C]4-Fluoro-N-methyl-N-(4-(6-(methylamino)pyrimidin-4-yl)thiazol-2-yl)benzamide ([11C]FIMX) is an effective radioligand for PET imaging of metabotropic glutamate receptor 1 (mGluR1) in monkey brain. Nucl Med Biol 42:967-74
Weidner, Lora D; Zoghbi, Sami S; Lu, Shuiyu et al. (2015) The Inhibitor Ko143 Is Not Specific for ABCG2. J Pharmacol Exp Ther 354:384-93
Brouwer, Chad; Jenko, Kimberly; Zoghbi, Sami S et al. (2014) Development of N-methyl-(2-arylquinolin-4-yl)oxypropanamides as leads to PET radioligands for translocator protein (18 kDa). J Med Chem 57:6240-51
Shrestha, Stal Saurav; Liow, Jeih-San; Lu, Shuiyu et al. (2014) (11)C-CUMI-101, a PET radioligand, behaves as a serotonin 1A receptor antagonist and also binds to ?(1) adrenoceptors in brain. J Nucl Med 55:141-6
Zanotti-Fregonara, Paolo; Zhang, Yi; Jenko, Kimberly J et al. (2014) Synthesis and Evaluation of Translocator 18 kDa Protein (TSPO) Positron Emission Tomography (PET) Radioligands with Low Binding Sensitivity to Human Single Nucleotide Polymorphism rs6971. ACS Chem Neurosci :
Lohith, Talakad G; Xu, Rong; Tsujikawa, Tetsuya et al. (2014) Evaluation in monkey of two candidate PET radioligands, [(11) C]RX-1 and [(18) F]RX-2, for imaging brain 5-HT4 receptors. Synapse :

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