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BackgroundIt is well recognized that the molar activity of a radioligand is an important pharmacokinetic parameter, especially in positron emission tomography (PET) of small animals. Occupation of a significant number of binding sites by radioligand molecules results in low radioligand accumulation in a target region (mass effect). Nevertheless, small-animal PET studies have often been performed without consideration of the molar activity or molar dose of radioligands. A simulation study would therefore help to assess the importance of the mass effect in small-animal PET. Here, we introduce a new compartmental model-based numerical method, which runs on commonly used spreadsheet software, to simulate the effect of molar activity or molar dose on the pharmacokinetics of radioligands.ResultsAssuming a two-tissue compartmental model, time-concentration curves of a radioligand were generated using four simulation methods and the well-known Runge–Kutta numerical method. The values were compared with theoretical values obtained under an ultra-high molar activity condition (pseudo-first-order binding kinetics), a steady-state condition and an equilibrium condition (second-order binding kinetics). For all conditions, the simulation method using the simplest calculation yielded values closest to the theoretical values and comparable with those obtained using the Runge–Kutta method. To satisfy a maximum occupancy less than 5%, simulations showed that a molar activity greater than 150 GBq/μmol is required for a model radioligand when 20 MBq is administered to a 250 g rat and when the concentration of binding sites in target regions is greater than 1.25 nM.ConclusionsThe simulation method used in this study is based on a very simple calculation and runs on widely used spreadsheet software. Therefore, simulation of radioligand pharmacokinetics using this method can be performed on a personal computer and help to assess the importance of the mass effect in small-animal PET. This simulation method also enables the generation of a model time-activity curve for the evaluation of kinetic analysis methods.

BackgroundMultidrug resistance-associated protein 1 (MRP1), an energy-dependent efflux pump, is expressed widely in various tissues and contributes to many physiological and pathophysiological processes. 6-Bromo-7-[11C]methylpurine ([11C]7m6BP) is expected to be useful for the assessment of MRP1 activity in the human brain and lungs. However, the radiochemical yield (RCY) in the synthesis of [11C]7m6BP was low, limiting its clinical application, because the methylation of the precursor with [11C]CH3I provided primarily the undesired isomer, 6-bromo-9-[11C]methylpurine ([11C]9m6BP). To increase the RCY of [11C]7m6BP, we investigated conditions for improving the [11C]7m6BP/[11C]9m6BP selectivity of the methylation reaction.Results[11C]7m6BP was manually synthesized via the methylation of 6-bromopurine with [11C]CH3I in various solvents and at different temperatures in the presence of potassium carbonate for 5 min. Several less polar solvents, including tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), and ethyl acetate (AcOEt) improved the [11C]7m6BP/[11C]9m6BP selectivity from 1:1 to 2:1, compared with the conventionally used solvents for the alkylation of 6-halopurines, acetone, acetonitrile, and N,N-dimethylformamide. However, a higher temperature (140 °C or 180 °C) was needed to progress the 11C-methylation in the less polar solvents, and the manual conditions could not be directly translated to an automated synthesis. [11C]Methyl triflate ([11C]CH3OTf) was thus used as a methylating agent to increase the conversion at a lower temperature. The 11C-methylation using [11C]CH3OTf at 100 °C proceeded efficiently in THF, 2-MeTHF, and AcOEt with maintenance of the improved selectivity. Starting from 28 to 34 GBq [11C]CO2, [11C]7m6BP was produced with 2.3–2.6 GBq for THF, 2.7–3.3 GBq for AcOEt, and 2.8–3.9 GBq for 2-MeTHF at approximately 30 min after the end of bombardment (n = 3 per solvent). The isolated RCYs (decay corrected) for THF, 2-MeTHF, and AcOEt were 24–28%, 29–35%, and 22–31% (n = 3), respectively.ConclusionsThe use of THF, 2-MeTHF, and AcOEt improved the [11C]7m6BP/[11C]9m6BP selectivity in the methylation reaction, and the improved method provided [11C]7m6BP with sufficient radioactivity for clinical use.

A disturbance in redox balance has been implicated in the pathogenesis of a number of diseases. This study sought to examine the feasibility of imaging brain redox status using a 11C-labeled dihydroquinoline derivative ([11C]DHQ1) for positron emission tomography (PET). The lipophilic PET tracer [11C]DHQ1 was rapidly oxidized to its hydrophilic form in mouse brain homogenate. The redox modulators diphenyleneiodonium and apocynin significantly reduced the initial velocity of [11C]DHQ1 oxidation, and apocynin also caused concentration-dependent inhibition of the initial velocity. Moreover, [11C]DHQ1 readily entered the brain by diffusion after administration and underwent oxidation into the hydrophilic cationic form, which then slowly decreased. By contrast, apocynin treatment inhibited the in vivo oxidation of [11C]DHQ1 to the hydrophilic cationic form, leading to a rapid decrease of radioactivity in the brain. Thus, the difference in the [11C]DHQ1 kinetics reflects the alteration in redox status caused by apocynin. In conclusion, [11C]DHQ1 is a potential PET tracer for imaging of redox status in the living brain.

Abstract Multidrug resistance–associated protein 1 (MRP1) transports various xenobiotics and metabolites across cell membranes, and the alteration of MRP1 expression is associated with certain lung diseases. This study sought to examine the feasibility of imaging pulmonary MRP1 activity using 6-bromo-7-[11C]methylpurine ([11C]1). A positron emission tomography study with [11C]1 was performed in wild-type, Mrp1 knockout (KO), and P-glycoprotein/breast cancer resistance protein (Pgp/Bcrp) KO mice. Lung radioactivity in wild-type and Mrp1 KO mice reached a maximum level immediately after the administration of [11C]1. Thereafter, radioactivity rapidly decreased in the lungs of wild-type mice, whereas it was mostly retained in the lungs of Mrp1 KO mice. The kinetics in the lungs of Pgp/Bcrp KO mice was quite similar to that of wild-type mice. Analysis of the chemical form confirmed that radioactive compounds in the lungs of Mrp1 KO mice were nearly completely composed of a glutathione conjugate, a MRP1 substrate, 5 minutes after the intravenous administration of [11C]1. The effect of an MRP1 inhibitor, MK571, on the kinetics of [11C]1 was also examined. Treatment with MK571 delayed the elimination of radioactivity from the lungs, compared with control mice. These results suggest that [11C]1 diffuses into the lung tissue after administration and undergoes conversion into the hydrophilic conjugate, which is then specifically expelled by MRP1. In conclusion, [11C]1 allows for the imaging of in vivo MRP1 activity in lungs.

After administration of the 99mTc complex with N,N'-1,2-ethylenediylbis-L-cysteine diethyl ester (99mTc-ECD), a brain perfusion imaging agent, the radioactive metabolite is trapped in primate brain, but not in mouse and rat. Here, we investigate the involvement of metabolite extrusion by organic anion transporter 3 (OAT3), which is highly expressed at the blood–brain barrier in mice, in this species difference. The efflux rate of radioactivity in the cerebrum of Oat3−/− mice at later phase was 20% of that of control mice. Thus, organic anion transporters in mouse brain would be involved in the low brain retention of radioactivity after 99mTc-ECD administration.

This study investigated differences in the color association with energy drinks between two populations in different cultures, i.e., Taiwanese and Japanese. An anonymous, self-administered paper questionnaire was administered to first- and second-year students at National Taiwan Normal University (Taiwan) and Naragakuen University (Japan). In our inter-country, gender-stratified comparison, the color selected most often in response to the question, “What color comes to your mind for energy drink label?” was red for the Taiwanese and blue for the Japanese. The color associations with energy drinks selected by 20% or more participants in at least one population and showing statistical difference were extracted as noticeable difference. The present study demonstrates that the color and energy drink functions are closely associated. Specifically, yellow and nourishment, black and stimulant, yellow and vitamin supplement, green and dietary fiber supplement, and red and iron supplement are tightly associated regardless of the country. The strong tie between cosmetic and white is specific to the Taiwanese consumers. This suggests that careful color selection based on consumers’ environmental and cultural backgrounds is important in communicating information regarding energy drink functions. It would be worth for energy drink manufacturers to consider those associations in designing labels for products.

Multidrug resistance-associated protein 1 (MRP1) acts as a defense mechanism by pumping xenobiotics and endogenous metabolites out of the brain. The currently available techniques for studying brain-to-blood efflux have significant limitations related to either their invasiveness or the qualitative assessment. Here, we describe an in vivo method, which overcomes these limitations for assessing MRP1 function, using positron emission tomography (PET) and a PET probe. 6-Bromo-7-[11C]methylpurine was designed to readily enter the brain after intravenous administration and to be efficiently converted to its glutathione conjugate (MRP1 substrate) in situ. Dynamic PET scan provided the brain time—activity curve after injection of 6-bromo-7-[11C]methylpurine into mice. The efflux rate of the substrate was kinetically estimated to be 1.4 h−1 with high precision. Moreover, knockout of Mrp1 gene caused approximately a 90% reduction of the efflux rate, compared with wild-type mice. In conclusion, our method allows noninvasive and quantitative assessment for MRP1 function in the living brain.

A disturbance in redox balance has been implicated in the pathogenesis of a number of diseases. This study sought to examine the feasibility of imaging brain redox status using a 11 C-labeled dihydroquinoline derivative ([ 11 C]DHQ1) for positron emission tomography (PET). The lipophilic PET tracer [ 11 C]DHQ1 was rapidly oxidized to its hydrophilic form in mouse brain homogenate. The redox modulators diphenyleneiodonium and apocynin significantly reduced the initial velocity of [ 11 C]DHQ1 oxidation, and apocynin also caused concentration-dependent inhibition of the initial velocity. Moreover, [ 11 C]DHQ1 readily entered the brain by diffusion after administration and underwent oxidation into the hydrophilic cationic form, which then slowly decreased. By contrast, apocynin treatment inhibited the in vivo oxidation of [ 11 C]DHQ1 to the hydrophilic cationic form, leading to a rapid decrease of radioactivity in the brain. Thus, the difference in the [ 11 C]DHQ1 kinetics reflects the alteration in redox status caused by apocynin. In conclusion, [ 11 C]DHQ1 is a potential PET tracer for imaging of redox status in the living brain.

A disturbance in redox balance has been implicated in the pathogenesis of a number of diseases. This study sought to examine the feasibility of imaging brain redox status using a super(11)C-labeled dihydroquinoline derivative ([ super(11)C]DHQ1) for positron emission tomography (PET). The lipophilic PET tracer [ super(11)C]DHQ1 was rapidly oxidized to its hydrophilic form in mouse brain homogenate. The redox modulators diphenyleneiodonium and apocynin significantly reduced the initial velocity of [ super(11)C]DHQ1 oxidation, and apocynin also caused concentration-dependent inhibition of the initial velocity. Moreover, [ super(11)C]DHQ1 readily entered the brain by diffusion after administration and underwent oxidation into the hydrophilic cationic form, which then slowly decreased. By contrast, apocynin treatment inhibited the in vivo oxidation of [ super(11)C]DHQ1 to the hydrophilic cationic form, leading to a rapid decrease of radioactivity in the brain. Thus, the difference in the [ super(11)C]DHQ1 kinetics reflects the alteration in redox status caused by apocynin. In conclusion, [ super(11)C]DHQ1 is a potential PET tracer for imaging of redox status in the living brain.

After administration of the super(99m)Tc complex with N,N'-1,2-ethylenediylbis-L-cysteine diethyl ester ( super(99m)Tc-ECD), a brain perfusion imaging agent, the radioactive metabolite is trapped in primate brain, but not in mouse and rat. Here, we investigate the involvement of metabolite extrusion by organic anion transporter 3 (OAT3), which is highly expressed at the blood-brain barrier in mice, in this species difference. The efflux rate of radioactivity in the cerebrum of Oat3 super(-/-) mice at later phase was 20% of that of control mice. Thus, organic anion transporters in mouse brain would be involved in the low brain retention of radioactivity after super(99m)Tc-ECD administration.