A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

Abstract Background Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff–Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high-performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, and biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 min after injection as represented by the area under the curve (AUC) and blood thiamine levels was investigated. Results The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61 ± 0.53 in the liver within 1 min, 18.67 ± 7.04 in the kidney within half a minute. The SUV dropped to 0.72 ± 0.05 and 0.77 ± 0.35 after 60 min of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 min after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 min was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = − 0.985, p = 0.015). Conclusion The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

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A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

10.21203/rs.3.rs-28109/v2 ◽

2020 ◽

Author(s):

Changpeng Wang ◽

Siwei Zhang ◽

Yuefei Zou ◽

Hongzhao Ma ◽

Donglang Jiang ◽

...

Keyword(s):

High Performance ◽

Specific Activity ◽

High Accumulation ◽

Metabolic Kinetics ◽

Thiamine Metabolism ◽

Pet Tracer ◽

The Status ◽

The Brain

Abstract Background: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity, radiochemical purity, radiochemical concentration, were evaluated by high performance liquid chromatography (HPLC). Metabolic kinetics and brain level of 18F-deoxy-thiamine in mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 minutes after injection as represented by the area under the curve (AUC) and blood thiamine levels were investigated. Results: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61±0.53 in the liver within 1 minute, 18.67±7.04 in the kidney within half a minute. The SUV dropped to 0.72±0.05 and 0.77±0.35 after 60 minutes of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 minutes after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency by thiamine-deprived diet (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 minutes was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = -0.985, p = 0.015).Conclusion: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

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A novel PET tracer 18F-deoxy-thiamine: synthesis, metabolic kinetics, and evaluation on cerebral thiamine metabolism status

10.21203/rs.3.rs-28109/v3 ◽

2020 ◽

Author(s):

Changpeng Wang ◽

Siwei Zhang ◽

Yuefei Zou ◽

Hongzhao Ma ◽

Donglang Jiang ◽

...

Keyword(s):

High Performance ◽

Specific Activity ◽

High Accumulation ◽

Metabolic Kinetics ◽

Thiamine Metabolism ◽

Pet Tracer ◽

The Status ◽

The Brain

Abstract Background: Some neuropsychological diseases are associated with abnormal thiamine metabolism, including Korsakoff-Wernicke syndrome and Alzheimer’s disease. However, in vivo detection of the status of brain thiamine metabolism is still unavailable and needs to be developed. Methods: A novel PET tracer of 18F-deoxy-thiamine was synthesized using an automated module via a two-step route. The main quality control parameters, such as specific activity and radiochemical purity, were evaluated by high performance liquid chromatography (HPLC). Radiochemical concentration was determined by radioactivity calibrator. Metabolic kinetics and the level of 18F-deoxy-thiamine in brains of mice and marmosets were studied by micro-positron emission tomography/computed tomography (PET/CT). In vivo stability, renal excretion rate, biodistribution of 18F-deoxy-thiamine in the mice were assayed using HPLC and γ-counter, respectively. Also, the correlation between the retention of cerebral 18F-deoxy-thiamine in 60 minutes after injection as represented by the area under the curve (AUC) and blood thiamine levels were investigated. Results: The 18F-deoxy-thiamine was stable both in vitro and in vivo. The uptake and clearance of 18F-deoxy-thiamine were quick in the mice. It reached the max standard uptake value (SUVmax) of 4.61±0.53 in the liver within 1 minute, 18.67±7.04 in the kidney within half a minute. The SUV dropped to 0.72±0.05 and 0.77±0.35 after 60 minutes of injection in the liver and kidney, respectively. After injection, kidney, liver, and pancreas exhibited high accumulation level of 18F-deoxy-thiamine, while brain, muscle, fat, and gonad showed low accumulation concentration, consistent with previous reports on thiamine distribution in mice. Within 90 minutes after injection, the level of 18F-deoxy-thiamine in the brain of C57BL/6 mice with thiamine deficiency (TD) was 1.9 times higher than that in control mice, and was 3.1 times higher in ICR mice with TD than that in control mice. The AUC of the tracer in the brain of marmosets within 60 minutes was 29.33 ± 5.15 and negatively correlated with blood thiamine diphosphate levels (r = - 0.985, p = 0.015).Conclusion: The 18F-deoxy-thiamine meets the requirements for ideal PET tracer for in vivo detecting the status of cerebral thiamine metabolism.

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A Novel Pet Tracer 18f-labeled Thiamine: Synthesis, Metabolic Kinetics, and Evaluation on Cerebral Thiamine Metabolism Status

10.21203/rs.3.rs-28109/v1 ◽

2020 ◽

Author(s):

Changpeng Wang ◽

Siwei Zhang ◽

Yuefei Zou ◽

Hongzhao Ma ◽

Donglang Jiang ◽

...

Keyword(s):

High Performance ◽

Metabolic Kinetics ◽

Thiamine Metabolism ◽

Pet Tracer ◽

Positron Emission ◽

Computer Tomography Imaging ◽

The Status ◽

Kinetics Of

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Cannabinoid effects on adenylate cyclase and phosphodiesterase activities of mouse brain

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y77-125 ◽

1977 ◽

Vol 55 (4) ◽

pp. 934-942 ◽

Cited By ~ 10

Author(s):

Thomas W. Dolby ◽

Lewis J. Kleinsmith

Keyword(s):

Cyclic Amp ◽

Adenylate Cyclase ◽

Mouse Brain ◽

Biogenic Amine ◽

Specific Activity ◽

Intraperitoneal Administration ◽

The Brain

The experiments presented in this paper examine the mechanisms underlying the ability of cannabinoids to alter the in vivo levels of cyclic adenosine 3′,5′-monophosphate (cyclic AMP) in mouse brain. It was found that changes in cyclic AMP levels are a composite result of direct actions of cannabinoids on adenylate cyclase (EC 4.6.1.1) activity and indirect actions involving the potentiation or inhibition of biogenic amine induced activity of adenylate cyclase. Furthermore, the long-term intraperitoneal administration of 1-(−)-Δ-tetrahydrocannabinol to mice produced a form of phosphodiesterase (EC 3.1.4.17) in the brain whose activity is not stimulated by Ca2+, although its basal specific activity is similar to that of control animals. In vitro, the presence of the cannabinoids caused no significant changes in activity of brain PDE at the concentrations tested. Some correlations are presented which imply that many of the observed behavioral and physiological actions of the cannabinoids in mammalian organisms may be mediated via cyclic AMP mechanisms.

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The influx of amino acids into the brain of the rat in vivo : the essential compared with some non-essential amino acids

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1973.0004 ◽

1973 ◽

Vol 183 (1070) ◽

pp. 59-70 ◽

Cited By ~ 65

Keyword(s):

Amino Acids ◽

Specific Activity ◽

Essential Amino Acids ◽

Transport Processes ◽

Carrier Mediated Transport ◽

A New Technique ◽

High Degree ◽

The Brain

The cerebral influx rates of fifteen amino acids were measured directly in living rats by means of a new technique which makes it possible to maintain a constant specific activity of a radioactively labelled amino acid in the bloodstream. A wide variation in the influx rates of the amino acids was found. These rates differed from those found by other workers using in vitro preparations, but are consistent with the theory that amino acids enter the brain mainly by carrier mediated transport processes with a high degree of specificity. There are a number of important differences between the behaviour of the transport processes in vivo and in vitro . The influx rates of the various amino acids were directly proportional to their concentrations in blood plasma (over the range of concentrations studied). All the nutritionally essential amino acids had relatively high influx rates as did other amino acids which the brain does not seem to be able to synthesize. On the other hand, amino acids that the brain can readily synthesize and two amino acids which are not normally found in mammalian tissues had low influx rates.

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A monoclonal antibody to oestradiol potentiates the stimulation of the specific activity of the brain type creatine kinase by oestrogen in vivo and in vitro

The Journal of Steroid Biochemistry and Molecular Biology ◽

10.1016/s0960-0760(97)00198-2 ◽

1998 ◽

Vol 64 (5-6) ◽

pp. 297-304 ◽

Cited By ~ 1

Author(s):

D. Sömjen ◽

Y. Amir-Zaltsman ◽

G. Mor ◽

B. Gayer ◽

S. Lichter ◽

...

Keyword(s):

Monoclonal Antibody ◽

Creatine Kinase ◽

Specific Activity ◽

The Brain ◽

Stimulation Of

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Studies on the toxicity of copper. I. The toxic action of copper in vivo and in vitro

Proceedings of the Royal Society of London Series B Biological Sciences ◽

10.1098/rspb.1966.0098 ◽

1966 ◽

Vol 166 (1004) ◽

pp. 273-284 ◽

Cited By ~ 16

Keyword(s):

Microsomal Fraction ◽

Specific Activity ◽

Membrane Surface ◽

High Specific Activity ◽

Rapid Onset ◽

Significant Inhibition ◽

Low Concentrations ◽

The Brain

With the object of throwing light upon the brain damage found in patients with Wilson’s disease (hepato-lenticular degeneration) due to the accumulation of copper, the effect of Cu 2+ has been investigated in pigeons. Subarachnoid injections of Cu 2+ (10 to 25 µ g) led to rapid onset of convulsions and death. These concentrations of Cu 2+ inhibited pigeon and rat b rain mitochondria; more organized tissue breis or slices showed no significant inhibition of oxygen up take at Cu +2 concentration inducing convulsions in vivo . Studies with radioactive copper ( 64 Cu) showed that the injected copper was widely distributed in the brain, though maximal near the site of injection. Centrifugation showed a high specific activity in the ATP -ase-rich microsomal fraction. Thorium in concentrations similar to Cu 2+ was not toxic. From this we suggest that the Cu 2+ does not alter the charge on some membrane surface. Since the effect of the copper is immediate, and since it does not affect respiration of slices in these low concentrations, we conclude that it is exerting its convulsive effect directly upon the cell surfaces.

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Biodistribution and Anticancer Characteristics of Les-3833, A Novel 4-thiazolidinone-Based Lead Compound

Scientia Pharmaceutica ◽

10.3390/scipharm88020018 ◽

2020 ◽

Vol 88 (2) ◽

pp. 18 ◽

Cited By ~ 1

Author(s):

Lesya Kobylinska ◽

Andrii Lozynskii ◽

Roman Lesyk ◽

Rostyslav Stoika ◽

Sandor G. Vari

Keyword(s):

Maximum Concentration ◽

High Performance ◽

Maximum Level ◽

Lead Compound ◽

Short Period ◽

Liquid Chromatography Tandem Mass ◽

Liver And Kidney ◽

The Brain

Recently, we identified the promising anticancer potential of the synthetic 4-thiazolidinone-based anticancer lead compound Les-3833 which demonstrated tumor-suppressing action in vitro and in vivo. Based on the results of previous studies, the aim of this research was to investigate the cytotoxicity in vitro and the biodistribution in laboratory mice to support the biotherapeutic drug development of Les-3833. Les-3833 (2.5 mg/kg) was intravenously injected into male Balb/c mice. Measurements were performed at 5 min, 15 min, 1 h, 4 h, and 24 h time points in blood plasma, brain, liver, and kidney using high-performance liquid chromatography/tandem mass spectrometry. After the administration of Les-3833, the maximum level of this compound was observed in plasma at 2.08 min. In the brain, the mean maximum concentration of Les-3833 was 7.17 ng/mL at 5 min, while after 15 min, it was not found. In the liver, at 5 min, the maximum concentration was 1190 ng/g. At 15 min, concentration of Les-3833 in the liver decreased by 14.3%; at 6 h by 22.8%; and after 24 h by 64.7%. Its maximum concentration in kidney was 404 ng/g within 5–15 min, at 1 h it decreased by 36.1%, and after 24 h by 49.3%. Thus, Les-3833 was rapidly taken up by different organs from the bloodstream, partially metabolized in the liver, and excreted mainly through the kidneys, while in the brain, a very low concentration could be observed for only a short period of time.

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Reduced Transaminase B (IlvE) Activity Caused by the Lack of yjgF Is Dependent on the Status of Threonine Deaminase (IlvA) in Salmonella enterica Serovar Typhimurium

Journal of Bacteriology ◽

10.1128/jb.186.3.803-810.2004 ◽

2004 ◽

Vol 186 (3) ◽

pp. 803-810 ◽

Cited By ~ 46

Author(s):

George Schmitz ◽

Diana M. Downs

Keyword(s):

Salmonella Enterica ◽

Specific Activity ◽

Acetolactate Synthase ◽

Threonine Deaminase ◽

Isoleucine Biosynthesis ◽

Serovar Typhimurium ◽

The Status ◽

Domains Of Life

ABSTRACT The YjgF/YER057c/UK114 family is a highly conserved class of proteins that is represented in the three domains of life. Thus far, a biochemical function demonstrated for these proteins in vivo or in vitro has yet to be defined. In several organisms, strains lacking a YjgF homolog have a defect in branched-chain amino acid biosynthesis. This study probes the connection between yjgF and isoleucine biosynthesis in Salmonella enterica. In strains lacking yjgF the specific activity of transaminase B, catalyzing the last step in the synthesis of isoleucine, was reduced. In the absence of yjgF, transaminase B activity could be restored by inhibiting threonine deaminase, the first enzymatic step in isoleucine biosynthesis. Strains lacking yjgF showed an increased sensitivity to sulfometruron methyl, a potent inhibitor of acetolactate synthase. Based on work described here and structural reports in the literature, we suggest a working model in which YjgF has a role in protecting the cell from toxic effects of imbalanced ketoacid pools.

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Effect of pH and inhibitors on beta-amyloid fibril assembly

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100166221 ◽

1996 ◽

Vol 54 ◽

pp. 752-753

Author(s):

Beverly E. Maleeff ◽

Timothy K. Hart ◽

Stephen J. Wood ◽

Ronald Wetzel

Keyword(s):

Amyloid Fibril ◽

Peptide Fragment ◽

Hydrophobic Peptides ◽

Amyloid Fibril Formation ◽

Effects Of Ph ◽

Severity Of The Disease ◽

Kinetics Of ◽

The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

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