Pharmacokinetic Modeling of (R)-[11C]verapamil to Measure the P-Glycoprotein Function in Nonhuman Primates

(R)-[(11)C]verapamil is a radiotracer widely used for the evaluation of the P-glycoprotein (P-gp) function at the blood-brain barrier (BBB). Several studies have evaluated the pharmacokinetics of (R)-[(11)C]verapamil in rats and humans under different conditions. However, to the best of our knowledge, the pharmacokinetics of (R)-[(11)C]verapamil have not yet been evaluated in nonhuman primates. Our study aims to establish (R)-[(11)C]verapamil as a reference P-gp tracer for comparison of a newly developed P-gp positron emission tomography (PET) tracer in a species close to humans. Therefore, the study assesses the kinetics of (R)-[(11)C]verapamil and evaluates the effect of scan duration and P-gp inhibition on estimated pharmacokinetic parameters. Three nonhuman primates underwent two dynamic 91 min PET scans with arterial blood sampling, one at baseline and another after inhibition of the P-gp function. The (R)-[(11)C]verapamil data were analyzed using 1-tissue compartment model (1-TCM) and 2-tissue compartment model fits using plasma-corrected for polar radio-metabolites or non-corrected for radio-metabolites as an input function and with various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (SE %) of the estimated parameters. 1-TCM was selected as the model of choice to analyze the (R)-[(11)C]verapamil data at baseline and after inhibition and for all scan durations tested. The volume of distribution (V(T)) and the efflux constant k(2) estimations were affected by the evaluated scan durations, whereas the influx constant K(1) estimations remained relatively constant. After P-gp inhibition (tariquidar, 8 mg/kg), in a 91 min scan duration, the whole-brain V(T) increased significantly up to 208% (p < 0.001) and K(1) up to 159% (p < 0.001) compared with baseline scans. The k(2) values decreased significantly after P-gp inhibition in all the scan durations except for the 91 min scans. This study suggests the use of K(1), calculated with 1-TCM and using short PET scans (10 to 30 min), as a suitable parameter to measure the P-gp function at the BBB of nonhuman primate

Pharmacokinetic Modeling of [ 18 F]MC225 for Quantification of the P-Glycoprotein Function at the Blood-Brain Barrier in Non-Human Primates with PET

[18F]MC225 has been developed as a weak substrate of P-glycoprotein (P-gp) aimed to measure changes in the P-gp function at the blood–brain barrier with positron emission tomography. This study evaluates [18F]MC225 kinetics in non-human primates and investigates the effect of both scan duration and P-gp inhibition. Three rhesus monkeys underwent two 91-min dynamic scans with blood sampling at baseline and after P-gp inhibition (8 mg/kg tariquidar). Data were analyzed using the 1-tissue compartment model (1-TCM) and 2-tissue compartment model (2-TCM) fits using metabolite-corrected plasma as the input function and for various scan durations (10, 20, 30, 60, and 91 min). The preferred model was chosen according to the Akaike information criterion and the standard errors (%) of the estimated parameters. For the 91-min scan duration, the influx constant K1 increased by 40.7% and the volume of distribution (VT) by 30.4% after P-gp inhibition, while the efflux constant k2 did not change significantly. Similar changes were found for all evaluated scan durations. K1 did not depend on scan duration (10 min—K1 = 0.2191 vs 91 min—K1 = 0.2258), while VT and k2 did. A scan duration of 10 min seems sufficient to properly evaluate the P-gp function using K1 obtained with 1-TCM. For the 91-min scan, VT and K1 can be estimated with a 2-TCM, and both parameters can be used to assess P-gp function

Heat Release Characteristics of Middle Temperature Latent Heat Storage Vessel by Means of Direct Contact Heat Exchange Method

Experiment has been performed of heat transfer characteristics of the middle temperature latent heat storage system of the direct-contact heat transfer by using m-E (meso-Erythritol, melting point of 119℃, latent heat of 375 kJ/kg) droplets as a latent heat storage material and silicone oil as a heat transfer medium. In the present study the liquid m-E was injected into the heat tranfer medium through a circular nozzle. The m-E droplets changed from liquid to solid phase during falling in the heat transfer medium at low temperature. From the measuring results of m-E droplet diameter, falling velocity, and solidification rate, the nondimensional empirical equations of the arithmetic mean diameter of the droplets and falling velocity, the solidification rate and the overall heat transfer coefficient were derived as a function of the characteristic arithmetic mean diameter, the terminal velocity, temperature and physical properties.近年、昼夜間の電力需要負荷平準化対策の一つとして、夜間等の余剰な電力を用いて、これを昼間に利用する潜熱蓄熱システムへの関心が高まりつつある。特に、固－液相変化潜熱蓄熱システムは、潜熱蓄熱材の凝固・融解潜熱を利用して蓄熱操作を行うため、蓄熱材単位質量当たりの貯蔵熱量が、水などの顕熱蓄熱システムと比較して大きくなり、同一熱量を蓄熱する場合、蓄熱槽の小型化が可能となる。さらに、その放熱過程において、熱媒体の取り出し温度が蓄熱材の融点近傍でほぼ一定となるため、一定温度水準での熱抽出に適している利点を有する。また、適当な融点を持つ潜熱物質を選択することにより、熱媒体取り出し温度レベルを自由に選択できることも潜熱蓄熱材の有する特徴の一つである。本研究においては、潜熱蓄熱材と熱媒体とは互いに不溶解な物質を選択し、両者を伝熱壁面を介さずに直接接触交換する形式の熱交換法を採用し、高密度の液相状態の潜熱蓄熱材をノズルから上部より、熱媒体槽中に噴射・注入して液滴として分散させる。分散した液滴状の蓄熱材が熱抽出用熱媒体との密度差により沈降しながら直接接触熱交換により、液滴表面より凝固相変化して潜熱放熱を行う際の熱特性を実験的に検討するものである。直接接触式熱交換法では、液滴群の表面が伝熱面に相当するので、単位面積当たりの伝熱面積が大きくなり、蓄熱槽のコンパクト化が可能である。また、構造が簡単で、隔壁を介さないため伝熱性能に優れ、他の熱交換法と比較して圧力損失が小さく、建設費が安価となり、保守が容易であるなどの特徴を持つ。本研究で採用する潜熱蓄熱材は、潜熱量の大きなメソ－エリスリトール（以下m-E,C4,H10,O4,固相密度1400kg/m3,融点Tm=119℃で融解潜熱L=375kj/kg）を採用し、m-E蓄熱材と不溶性なシリコン油を熱抽出媒体とした。実験は、蓄熱状態の液状m-E蓄熱材をノズルから熱抽出媒体としてのシリコン油槽中にスプレー状に噴射・沈降した場合の液相状態のm-E蓄熱材の直接接触凝固による放熱特性にえいきょうを及ぼす諸因子の効果を検討したものである

Evaluation of D-isomers of 4-borono-2-18F-fluoro-phenylalanine and O-11C-methyl-tyrosine as brain tumor imaging agents: a comparative PET study with their L-isomers in rat brain glioma

Abstract Background The potential of the D-isomerization of 4-borono-2-18F-fluoro-phenylalanine (18F-FBPA) to improve its target tumor to non-target normal brain tissue ratio (TBR) was evaluated in rat brain glioma and compared with those of L- and D-11C-methyl-tyrosine (11C-CMT). The L- or D-isomer of 18F-FBPA was injected into rats through the tail vein, and their whole body kinetics and distributions were assessed using the tissue dissection method up to 90 min after the injection. The kinetics of L- and D-18F-FBPA or L- and D-11C-CMT in the C-6 glioma-inoculated rat brain were measured for 90 or 60 min, respectively, using high-resolution animal PET, and their TBRs were assessed. Results Tissue dissection analyses showed that D-18F-FBPA uptake was significantly lower than that of L-18F-FBPA in the brain and abdominal organs, except for the kidney and bladder, reflecting the faster elimination rate of D-18F-FBPA than L-18F-FBPA from the blood to the urinary tract. PET imaging using 18F-FBPA revealed that although the brain uptake of D-18F-FBPA was significantly lower than that of L-18F-FBPA, the TBR of the D-isomer improved to 6.93 from 1.45 for the L-isomer. Similar results were obtained with PET imaging using 11C-CMT with a smaller improvement in TBR to 1.75 for D-11C-CMT from 1.33 for L-11C-CMT. Conclusions The present results indicate that D-18F-FBPA is a better brain tumor imaging agent with higher TBR than its original L-isomer and previously reported tyrosine-based PET imaging agents. This improved TBR of D-18F-FBPA without any pre-treatments, such as tentative blood-brain barrier disruption using hyperosmotic agents or sonication, suggests that the D-isomerization of BPA results in the more selective accumulation of 10B in tumor cells that is more effective and less toxic than conventional L-BPA