Numerical simulation method for the assessment of the effect of molar activity on the pharmacokinetics of radioligands in small animals.

Background: It 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.

Efficient Reductive N-C-Methylation Using Arylamines or Alkylamines and In Situ-Generated [C]Formaldehyde From [C]Methyl Iodide.

Reductive N-C-methylation using [C]formaldehyde and amines has been used to prepare N-C-methylated compounds. However, the yields of the N-C-methylated compounds are often insufficient. In this study, we developed an efficient method for base-free reductive N-C-methylation that is applicable to a wide variety of substrates, including arylamines bearing electron-withdrawing and electron-donating substituents.

Improved synthesis of 6-bromo-7-[C]methylpurine for clinical use.

Background: Multidrug 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-[C]methylpurine ([C]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 [C]7m6BP was low, limiting its clinical application, because the methylation of the precursor with [C]CHI provided primarily the undesired isomer, 6-bromo-9-[C]methylpurine ([C]9m6BP).

Evaluation and improvement of CuI-mediated C-cyanation.

CuI-mediated C-cyanation was evaluated by synthesizing [ C]perampanel ([ C]5) as a model compound and compared with previous reports. To a DMF solution with 5'-(2-bromophenyl)-1'-phenyl-[2,3'-bipyridin]-6'(1'H)-one (4) and CuI, [ C]NH CN in a stream of ammonia/nitrogen (5:95, v/v) gas was bubbled. Subsequently, the reaction mixture was heated at 180°C for 5 min.

C-Labeled Radiotracer for Noninvasive and Quantitative Assessment of the Thiocyanate Efflux System in the Brain.

Thiocyanate (SCN) alters the potency of certain agonists for the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and dysfunctions in AMPA receptor signaling are considered to underlie a number of neurological diseases. While humans may be exposed to SCN from the environment, including food sources, a carrier-mediated system transports SCN from the brain into the blood and is an important regulator of SCN distribution in the central nervous system. The assessment of this SCN efflux system in the brain would thus be useful for understanding the mechanisms underlying the neurotoxicity of SCN and for elucidating the relationship between the efflux system and brain diseases.

Rapid 'on-column' preparation of hydrogen [C]cyanide from [C]methyl iodide [C]formaldehyde.

Hydrogen [C]cyanide ([C]HCN) is a versatile C-labelling agent for the production of C-labelled compounds used for positron emission tomography (PET). However, the traditional method for [C]HCN production requires a dedicated infrastructure, limiting accessibility to [C]HCN. Herein, we report a simple and efficient [C]HCN production method that can be easily implemented in C production facilities.

Country and Gender Differences in the Color Association with Energy Drinks: A Survey in Taiwanese and Japanese Students.

This study investigated differences in the color association with energy drinks between two populations in different cultures, i.e., Taiwanese and Japanese.

6-[I]Iodo-9-pentylpurine for Imaging the Activity of the Sodium Iodide Symporter in the Brain.

Iodide homeostasis and thyroid hormone metabolism in the brain are potentially related to changes in the activity of the sodium iodide symporter (NIS). No radiotracers are currently available for imaging brain NIS activity. Here, we synthesized 6-[I]iodo-9-pentylpurine that can noninvasively measure iodide efflux from the brain and showed that the efflux rate of [I]I in NIS knockout mice was 84% lower than that of wild-type mice.

Mechanisms of glutathione-conjugate efflux from the brain into blood: Involvement of multiple transporters in the course.

Accumulation of detrimental glutathione-conjugated metabolites in the brain potentially causes neurological disorders, and must therefore be exported from the brain. However, in vivo mechanisms of glutathione-conjugates efflux from the brain remain unknown. We investigated the involvement of transporters in glutathione-conjugates efflux using 6-bromo-7-[C]methylpurine ([C]), which enters the brain and is converted into its glutathione conjugate, -(7-[C]methylpurin-6-yl)glutathione ([C]).

Kinetics and metabolism of apocynin in the mouse brain assessed with positron-emission tomography.

Background: Apocynin is a constituent of the medicinal herb Picrorhiza kurroa. It is an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase. This compound shows potential anti-inflammatory and antioxidant effects and has been tested as a neuroprotectant in many animal models of brain disease.

Benzyl [(11)C]Hippurate as an Agent for Measuring the Activities of Organic Anion Transporter 3 in the Brain and Multidrug Resistance-Associated Protein 4 in the Heart of Mice.

Multidrug resistance-associated protein 4 (MRP4) and organic anion transporter 3 (OAT3) mediate the efflux of organic anions from the brain and heart. In this study, we have developed a probe for estimating the activity of these transporters in these tissues using positron emission tomography. Several (11)C-labeled hippuric acid ester derivatives were screened with the expectation that they would be hydrolyzed in situ to form the corresponding (11)C-labeled organic acids in target tissues.

In-vivo imaging of blood-brain barrier permeability using positron emission tomography with 2-amino-[3-11C]isobutyric acid.

Objective: The blood-brain barrier (BBB) limits the entry of some therapeutics into the brain, resulting in reduced efficacy. BBB-opening techniques have been developed to enhance the entry into the brain. However, a noninvasive, highly sensitive and quantitative method for evaluating the changes in BBB permeability induced by such techniques is needed to optimize treatment protocols.

A ¹¹C-labeled 1,4-dihydroquinoline derivative as a potential PET tracer for imaging of redox status in mouse 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.

OAT3-mediated extrusion of the 99mTc-ECD metabolite in the mouse brain.

After administration of the (99m)Tc complex with N,N'-1,2-ethylenediylbis-L-cysteine diethyl ester ((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(-/-) mice at later phase was 20% of that of control mice.

Development of purine-derived 18F-labeled pro-drug tracers for imaging of MRP1 activity with PET.

Multidrug resistance-associated protein 1 (MRP1) is a drug efflux transporter that has been implicated in the pathology of several neurological diseases and is associated with development of multidrug resistance. To enable measurement of MRP1 function in the living brain, a series of 6-halopurines decorated with fluorinated side chains have been synthesized and evaluated as putative pro-drug tracers. The tracers were designed to undergo conjugation with glutathione within the brain and hence form the corresponding MRP1 substrate tracers in situ.

PET probes for imaging brain acetylcholinesterase.

Imaging acetylcholinesterase (AChE) is valuable not only for diagnosing and understanding dementia but also for monitoring the effects of cholinesterase inhibitors used as antidementia drugs and for determining the appropriate clinical dosage of newly developed cholinesterase inhibitors. The distribution of AChE in the living brain can be imaged with two different types of radioprobes, including substrate-type and ligand-type probes. The substrate-type positron emission tomography (PET) probes, N-[(11) C]methylpiperidin-4-yl acetate ([(11) C]MP4A), and its propionate, [(11) C]MP4P, have been widely used in clinical studies of dementia, including Alzheimer's disease.

Improvement of brain uptake for in vivo PET imaging of astrocytic oxidative metabolism using benzyl [1-(11)C]acetate.

Brain uptake of acetate is insufficient for obtaining a quantitative image of astrocytic oxidative metabolism. To improve the brain uptake of [1-(11)C]acetate, we synthesized benzyl [1-(11)C]acetate ([1-(11)C]BA) and conducted a positron emission tomography (PET) study assessing astrocytic oxidative metabolism. The brain uptake of [1-(11)C]BA was markedly higher compared with [1-(11)C]acetate, and disappeared with a half-life of 20 min in all regions studied.

Imaging of activity of multidrug resistance-associated protein 1 in the lungs.

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-[(11)C]methylpurine ([(11)C]1). A positron emission tomography study with [(11)C]1 was performed in wild-type, Mrp1 knockout (KO), and P-glycoprotein/breast cancer resistance protein (Pgp/Bcrp) KO mice.

Effects of halogenation on tyrosine phosphorylation and peptide binding to the SRC homology 2 domain of lymphocyte-specific protein tyrosine kinase.

Phosphorylation of tyrosine residues by protein tyrosine kinases (PTK) and phosphotyrosine/Src homology 2 (SH2) domain interactions are crucial not only for signal transduction but also for regulation of PTK activity. Tyrosine residues also receive nitration and halogenation under oxidative conditions. It has been reported that nitration of tyrosine residue caused peptides to be a poor substrate for PTK and that nitrotyrosine residues could bind to SH2 domains as a phosphotyrosine mimic to activate Src family kinase.

Efficient synthesis and chiral separation of 11C-labeled ibuprofen assisted by DMSO for imaging of in vivo behavior of the individual isomers by positron emission tomography.

The pharmacological mechanisms focusing on chiral isomer of ibuprofen are not fully understood. Only the (S)-isomer of ibuprofen inhibits cyclooxygenases, which mediates the generation of prostanoids and thromboxanes. Consequently, (S)-isomers represent a major promoter of the anti-inflammatory effect, and the effects of the (R)-isomers have not been widely discussed.

Effect of radiolabeled metabolite elimination from the brain on the accuracy of cerebral enzyme activity estimation using positron emission tomography with substrate tracers.

Cerebral enzyme activity can be quantified using positron emission tomography (PET) in conjunction with a radiolabeled enzyme substrate. We investigated the relationship between the elimination rate (k(el)) of tracer metabolites from the brain and the precision of target enzyme activity estimation (k(3)). An initial simulation study indicated that the precision of k(3) estimates was highly dependent on k(el), and was characterized by several kinetic parameters including the ratio of k(el) and the efflux rate (k(2)) of authentic tracer (β≡k(el)/k(2)).

Piperidine-4-methanthiol ester derivatives for a selective acetylcholinesterase assay.

The activity of acetylcholinesterase (AChE) is measured to obtain pathological information about the cholinergic system in various disease states and to assess the effect of AChE inhibitors. Using Ellman's method that is commonly used in such examinations, butyrylcholinesterase inhibitors must be added to measure AChE-specific activity because of low selectivity of AChE toward traditional substrates; however, such inhibitors also inhibit AChE. Therefore, it is desirable to obtain an AChE selective substrate that can be used with the Ellman's method.

Use of a novel radiometric method to assess the inhibitory effect of donepezil on acetylcholinesterase activity in minimally diluted tissue samples.

Background And Purpose: Cholinesterase inhibitors have been widely used for the treatment of patients with dementia. Monitoring of the cholinesterase activity in the blood is used as an indicator of the effect of the cholinesterase inhibitors in the brain. The selective measurement of cholinesterase with low tissue dilution is preferred for accurate monitoring; however, the methods have not been established.

Reactivity of 6-halopurine analogs with glutathione as a radiotracer for assessing function of multidrug resistance-associated protein 1.

6-Bromo-7-[(11)C]methylpurine is reported to react with glutathione via glutathione S-transferases in the brain and to be converted into a substrate for multidrug resistance-associated protein 1 (MRP1), an efflux pump. The compound with a rapid conversion rate allows quantitative assessment of MRP1 function, but this rate is probably susceptible to interspecies differences. Hence, for application to different species, including humans, it is necessary to adjust the conversion rate by modifying the chemical structure.

In vivo evaluation of N-[18F]fluoroethylpiperidin-4ylmethyl acetate in rats compared with MP4A as a probe for measuring cerebral acetylcholinesterase activity.

[(11)C]MP4A is an established radioprobe for quantification of cerebral acetylcholinesterase (AChE) activity by positron emission tomography (PET) based on the kinetics of AChE-mediated metabolism and metabolite trapping. It has been used to assess the deficiency in cholinergic innervation in the brain of patients with dementia. Because (18)F has a longer half-life than (11)C, (18)F-labeled derivatives of [(11)C]MP4A allow delivery of the probe to other PET centers, making AChE measurement more widely applicable.