Distribution of carbon-11 labeled methamphetamine and the effect of its chronic administration in mice

doi:10.1016/0969-8051(93)90080-E

Nuclear Medicine and Biology

Volume 20, Issue 4, May 1993, Pages 487-492

https://doi.org/10.1016/0969-8051(93)90080-E Get rights and content

Abstract

[¹¹C]Methamphetamine, a psychotropic agent, was synthesized by N-methylation of amphetamine with [¹¹C]CH₃I in hopes that it could be applied in the near future to assist positron emission tomography (PET) in the imaging of its distribution in the human brain. The regional distribution of [¹¹C]methamphetamine was investigated in the mice brain at various intervals after an intravenous (i.v.) injection. Radioactivity was higher in the hypothalamus, cortex, striatum and hippocampus. Furthermore, in chronically administered mice, the uptake of [¹¹C]methamphetamine was higher in the striatum than those in other regions. The regional differences in the distribution of methamphetamine in the mice brain may enable the imaging of its distribution by PET using [¹¹C]methamphetamine.

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Methamphetamine toxicity-induced calcineurin activation, nuclear translocation of nuclear factor of activated T-cells and elevation of cyclooxygenase 2 levels are averted by calpastatin overexpression in neuroblastoma SH-SY5Y cells
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Citation Excerpt :
METH at 1 mM migh represent accumulation or retention of drugs in the brain. It has been reported that methamphetamine is homogenously administered in brain of animals exposed acutely to the drugs and some preferential accumulation or retention might occur in dopamine nerve terminals in the striatum (Mizugaki et al., 1993). The results from the present study demonstrated that calpastatin overexpression can reduce the neurotoxic effect of METH on a reduction in cell viability, an induction in the CaN-NFAT signaling pathway, increase in apoptotic cell death and the amount of COX-2 expression.
Methamphetamine (METH) is an addictive stimulant drug that has many negative consequences, including toxic effects to the brain. Recently, the induction of inflammatory processes has been identified as a potential contributing factor to induce neuronal cell degeneration. It has been demonstrated that the expression of inflammatory agents, such as cyclooxygenase 2 (COX-2), depends on the activation of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT). Moreover, the excessive elevation in cytosolic Ca²⁺ levels activates the cell death process, including calpain activation in neurons, which was diminished by the overexpression of the calpain inhibitor protein, calpastatin. However, it is unclear whether calpain mediates CaN-NFAT activation in the neurotoxic process. In the present study, we observed that the toxic high dose of METH-treated neuroblastoma SH-SY5Y cells significantly decreased cell viability but increased apoptotic cell death, the active cleaved form of calcineurin, the nuclear translocation of NFAT, and COX-2 levels. Nevertheless, these toxic effects were diminished in METH-treated calpastatin-overexpressing SH-SY5Y cells. These findings might emphasize the role of calpastatin against METH-induced toxicity by a mechanism related to calpain-dependent CaN-NFAT activation-induced COX-2 expression.
Increased plasma concentration and brain penetration of methamphetamine in behaviorally sensitized rats
2003, European Journal of Pharmacology
Exposure to methamphetamine causes behavioral sensitization in experimental animals. However, the precise mechanism of this behavioral sensitization has not yet been fully elucidated. Accordingly, we evaluated the pharmacokinetic properties of methamphetamine in rats behaviorally sensitized to methamphetamine following its repeated administration (6 mg/kg, i.p., once a day for 5 days followed by a 21-day drug abstinence period). In the sensitized rats, methamphetamine (0.8 mg/kg)-induced locomotor activity was significantly enhanced, suggesting the successful establishment of behavioral sensitization to methamphetamine. Significant increases in the concentrations of methamphetamine in plasma and brain dialysate, as well as the delayed disappearance of methamphetamine from plasma, were observed in the sensitized rats after intravenous injection of methamphetamine (5 mg/kg). The tissue to plasma concentration ratio (Kp) of methamphetamine in lung and heart decreased in the sensitized rats. The renal excretion of methamphetamine, which is sensitive to several cations, was also decreased in the sensitized rats. Moreover, in the sensitized rats, the expression of organic cation transporter 3 (OCT3) mRNA was decreased in kidney, brain and heart as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Taken together, these results suggest that the behavioral outcome of sensitization to methamphetamine might, in part, be due to the increased levels of methamphetamine in plasma and brain extracellular areas, as well as an altered tissue distribution of methamphetamine associated with changes in the cation transport system.
Influence of anesthesia on brain distribution of [11C]methamphetamine in monkeys in positron emission tomography (PET) study
2001, Brain Research
We investigated the influence of anesthesia on the brain distribution of [¹¹C]methamphetamine (MAP) obtained by the positron emission tomography (PET) using the normal rhesus monkeys. We clarified that the brain uptake of [¹¹C]MAP under halothane anesthesia was faster and higher than that under pentobarbital. The difference of the effect of anesthesia is an important problem in pharmacokinetic study in PET with experimental animals.
Regional distribution of methamphetamine in autopsied brain of chronic human methamphetamine users
2001, Forensic Science International
We measured levels of methamphetamine and those of its metabolite amphetamine in 15 autopsied brain regions of 14 human methamphetamine users. Only slight regional differences were observed in drug concentrations among the brain areas. Although, some redistribution of the drugs probably occurred postmortem, these data suggest that methamphetamine might not be preferentially retained in dopamine-rich brain areas but is heterogenously distributed in brain of chronic human users of the drug. The possible pharmacological actions of methamphetamine in both dopamine-rich and poor brain areas of chronic drug users need to be considered.
The synthesis of (R)- and (S)-[N-methyl-11C]β, β- difluoromethamphetamine for the investigation of the binding mechanism of biogenic amines in vivo
1999, Applied Radiation and Isotopes
In an attempt to elucidate the contribution of the extent of nitrogen protonation on the in vivo binding of methamphetamine in the brain, the enantiomers of [N-methyl-¹¹C]β,β-difluoroamphetamine (4) were prepared for use in positron emission tomography (PET) studies. Thus, the enantiomers of β,β-difluoroamphetamine were prepared from trans-β-methylstyrene, via bromination, conversion into the azirine, fluorination and resolution as the tartrate salts. (R)- and (S)-β,β-difluoroamphetamine (3) were then each labelled with carbon-11 (t_1/2=20.4 min) by N-methylation of the corresponding homochiral β,β-difluoroamphetamine with [¹¹C]methyl iodide. The labelled products were each synthesised, purified and formulated in 35 min, starting from [¹¹C]carbon dioxide in 15–16% decay-corrected radiochemical yield, with a radiochemical purity of >99% and specific radioactivity of 50–150 GBq μmol⁻¹ at end of synthesis.
Effects of haloperidol and cocaine pretreatments on brain distribution and kinetics of [11C]methamphetamine in methamphetamine sensitized dog: Application of PET to drug pharmacokinetic study
1997, Nuclear Medicine and Biology
Repeated administration of methamphetamine (MAP) causes behavioral sensitization in animals. We previously reported that the maximum accumulation level of [¹¹C]MAP in the MAP-sensitized dog brain was 1.4 times higher than that in the control. In behavioral studies, haloperidol (a dopamine D₂ receptor antagonist) prevents MAP-induced behavioral sensitization, and cocaine (a dopamine reuptake blocker) has the cross-behavioral sensitization with MAP. In the present study, to elucidate the relation between the MAP-induced behavioral sensitization and the pharmacokinetics of MAP, we investigated the effects of haloperidol and cocaine pretreatments on brain regional distribution and kinetics of [¹¹C]MAP using positron emission tomography (PET). A significant increase of [¹¹C]MAP uptake into the sensitized dog brain was prevented by haloperidol and cocaine pretreatments. These pharmacokinetic changes were not due to the changes in the rate of MAP metabolism. These results suggest haloperidol and cocaine can change the cerebral pharmacokinetic profile of MAP in the behavioral-sensitized dog. The variations of MAP-accumuation may affect the development or expression of MAP-induced behavioral sensitization.

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Nuclear Medicine and Biology

Abstract

References (14)

Distribution of [¹⁴C]amphetamine in mouse brain: an autoradiographic study

Brain Res.

Biodistribution of ¹¹C-methamphetamine in tissue of mice

The disposition of [³H]norepinephrine, [³H]dopamine and [³H]dopa in various regions of the brain

J. Neurochem.

Visualization of neural transmission in dopaminergic neurons of dog brain using PET

Characteristics of [³H]( + )-Amphetamine binding sites in the rat central nervous system

Life Sci.

Relation of pharmacological and behavioral effects of a hallucinogenic amphetamine to distribution in cat brain

Science

Remote-controlled synthesis of ¹¹C-iodomethane for the practical preparation of ¹¹C-labeled radiopharmaceuticals

Int. J. Appl. Radiat. Isot.

Cited by (15)

Methamphetamine toxicity-induced calcineurin activation, nuclear translocation of nuclear factor of activated T-cells and elevation of cyclooxygenase 2 levels are averted by calpastatin overexpression in neuroblastoma SH-SY5Y cells

Increased plasma concentration and brain penetration of methamphetamine in behaviorally sensitized rats

Influence of anesthesia on brain distribution of [<sup>11</sup>C]methamphetamine in monkeys in positron emission tomography (PET) study

Regional distribution of methamphetamine in autopsied brain of chronic human methamphetamine users

The synthesis of (R)- and (S)-[N-methyl-<sup>11</sup>C]β, β- difluoromethamphetamine for the investigation of the binding mechanism of biogenic amines in vivo

Effects of haloperidol and cocaine pretreatments on brain distribution and kinetics of [<sup>11</sup>C]methamphetamine in methamphetamine sensitized dog: Application of PET to drug pharmacokinetic study

Distribution of carbon-11 labeled methamphetamine and the effect of its chronic administration in mice

Abstract

Brain Res.

Biodistribution of 11C-methamphetamine in tissue of mice

The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain

J. Neurochem.

Visualization of neural transmission in dopaminergic neurons of dog brain using PET

Characteristics of [3H]( + )-Amphetamine binding sites in the rat central nervous system

Life Sci.

Relation of pharmacological and behavioral effects of a hallucinogenic amphetamine to distribution in cat brain

Science

Remote-controlled synthesis of 11C-iodomethane for the practical preparation of 11C-labeled radiopharmaceuticals

Int. J. Appl. Radiat. Isot.

Biodistribution of ¹¹C-methamphetamine in tissue of mice

The disposition of [³H]norepinephrine, [³H]dopamine and [³H]dopa in various regions of the brain

Characteristics of [³H]( + )-Amphetamine binding sites in the rat central nervous system

Remote-controlled synthesis of ¹¹C-iodomethane for the practical preparation of ¹¹C-labeled radiopharmaceuticals