17 research outputs found
Subanesthetic IV ketamine reduces acute suicidal ideation in patients with mood disorders
Background. Depression and suicide are common in the United States and present a significant problem in the healthcare landscape. Currently, there are few options that can rapidly reduce suicidal ideation in patients with depression. Ketamine, a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to reduce acute suicidality in patients with depression. Previous studies have a reduction of suicidal ideation compared to saline placebo, but few studies have shown a significant effect compared to a similar psychoactive drug such as midazolam.
Method. A search of PubMed and PsychNET was performed in September 2018 using the terms âketamine,â âsuicide,â and âdepressionâ with a filter for human clinical trials. Three randomized controlled trials were discovered that compared the effects of intravenous (IV) ketamine or midazolam on active, acute suicidal ideation in patients with a history of depression. Suicidal ideation and depression were measured using similar scales to allow for relative comparison between studies. Baseline measurements of suicidal ideation were assessed before IV administration of the randomized medications, and repeat assessments were obtained 24 hours after administration of the medication.
Results. All three studies evaluated showed a reduction in suicidal ideation in patients that received ketamine compared to those that received midazolam. Grunebaum et al. and Price et al. both saw statistically significant reductions in SI in patients who received ketamine and assessed with the Beck Scale for Suicidal Ideation (BSI) or the Scale for Suicidal Ideation (SSI). Murrough et al. observed a nonsignificant reduction in SI at 24 hours using the BSI, but did see a statistically significant reduction using the Montgomery-Asberg Depression Rating Scale (MADRS-SI). SI was reduced in the midazolam group in all studies, but none were significant, and none as extensive as the ketamine groups.
Conclusion. Ketamine administered at subanesthetic doses can provide acute relief of suicidal ideation in patients with depression within 24 hours
Is metabotropic glutamate receptor 5 upregulated in prefrontal cortex in fragile X syndrome?
Abstract
Background:
Fragile X syndrome (FXS) is a common inherited form of intellectual disability caused by loss of function of the fragile X mental retardation protein. Recent animal studies suggest that upregulated downstream signaling by metabotropic glutamate receptor 5 (mGluR5) might be an important mechanism for cognitive and behavioral abnormalities associated with FXS. However, mGluR5 density in human FXS remains unknown.
Methods:
Receptor binding and protein expression were measured in the postmortem prefrontal cortex of 14 FXS patients or carriers and 17 age- and sex-matched control subjects without neurological disorders. In-vitro binding assays were performed using [[superscript 3]H]-labeled 3-methoxy-5-pyridin-2-ylethynylpyridine (MPEPy), a selective and high-affinity negative allosteric modulator of mGluR5, to measure receptor density and the radioligand’s dissociation constant, which is inversely proportional to affinity. Immunoblotting was also performed, to measure mGluR5 protein expression.
Results:
The mGluR5 density increased with marginal significance (+16%; P = 0.058) in the prefrontal cortex of FXS patients or carriers compared with matched healthy controls. No significant change in dissociation constant (-4%; P = 0.293) was observed. Immunoblotting found a significant elevation (+32%; P = 0.048) in mGluR5 protein expression.
Conclusions:
Both mGluR5 binding density and protein expression were increased in the brains of FXS patients or carriers, but only expression was significantly different, which could be because of the small sample size and moderate variability. Another important caveat is that the effects of psychotropic medications on mGluR5 expression are largely unknown. Future in-vivo measurement of mGluR5 with positron emission tomography might characterize the role of this receptor in the pathophysiology of FXS and facilitate trials of mGluR5-oriented treatments for this disorder.National Institute of Mental Health (U.S.)National Institutes of Health (U.S.) (IRP-NIMHNIH
Development of <i>N</i>âMethyl-(2-arylquinolin-4-yl)oxypropanamides as Leads to PET Radioligands for Translocator Protein (18 kDa)
Translocator protein (18 kDa), known
as TSPO, is a recognized biomarker
of neuroinflammation. Radioligands with PET accurately quantify TSPO
in neuroinflammatory conditions. However, the existence of three human
TSPO genotypes that show differential affinity to almost all useful
TSPO PET radioligands hampers such studies. There is an unmet need
for genotype-insensitive, high-affinity, and moderately lipophilic
TSPO ligands that may serve as leads for PET radioligand development.
To address this need, we varied the known high-affinity TSPO ligand
(<i>l</i>)-<i>N</i>,<i>N</i>-diethyl-2-methyl-3-(2-phenylquinolin-4-yl)Âpropanamide
in its aryl scaffold, side chain tether, and pendant substituted amido
group while retaining an <i>N</i>-methyl group as a site
for labeling with carbon-11. From this effort, oxygen-tethered <i>N</i>-methyl-aryloxypropanamides emerged as new high-affinity
TSPO ligands with attenuated lipophilicity, including one example
with attractive properties for PET radioligand development, namely <i>N</i>-methyl-<i>N</i>-phenyl-2-{[2-(pyridin-2-yl)Âquinolin-4-yl]Âoxy}Âpropanamide
(<b>22a</b>; rat <i>K</i><sub>i</sub> = 0.10 nM; human
TSPO genotypes <i>K</i><sub>i</sub> = 1.4 nM; clogD = 4.18)
2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PETâSynthesis, Triage, and Radiolabeling
Cyclooxygenase 2 (COX-2) is an inducible enzyme responsible for the conversion of arachidonic acid into the prostaglandins, PGG2 and PGH2. Expression of this enzyme increases in inflammation. Therefore, the development of probes for imaging COX-2 with positron emission tomography (PET) has gained interest because they could be useful for the study of inflammation in vivo, and for aiding anti-inflammatory drug development targeting COX-2. Nonetheless, effective PET radioligands are still lacking. We synthesized eleven COX-2 inhibitors based on a 2(4-methylsulfonylphenyl)pyrimidine core from which we selected three as prospective PET radioligands based on desirable factors, such as high inhibitory potency for COX-2, very low inhibitory potency for COX-1, moderate lipophilicity, and amenability to labeling with a positron-emitter. These inhibitors, namely 6-methoxy-2-(4-(methylsulfonyl)phenyl-N-(thiophen-2ylmethyl)pyrimidin-4-amine (17), the 6-fluoromethyl analogue (20), and the 6-(2-fluoroethoxy) analogue (27), were labeled in useful yields and with high molar activities by treating the 6-hydroxy analogue (26) with [11C]iodomethane, [18F]2-fluorobromoethane, and [d2-18F]fluorobromomethane, respectively. [11C]17, [18F]20, and [d2-18F]27 were readily purified with HPLC and formulated for intravenous injection. These methods allow these radioligands to be produced for comparative evaluation as PET radioligands for measuring COX-2 in healthy rhesus monkey and for assessing their abilities to detect inflammation
Synthesis and evaluation of new TSPO PET radioligands with low sensitivity to human genotype
3âSubstituted 1,5-Diarylâ1<i>H</i>â1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COXâ1 in Monkey. Part 1: Synthesis and Pharmacology
Cyclooxygenase-1
(COX-1) is a key enzyme in the biosynthesis of
proinflammatory thromboxanes and prostaglandins and is found in glial
and neuronal cells within brain. COX-1 expression is implicated in
numerous neuroinflammatory states. We aim to find a direct-acting
positron emission tomography (PET) radioligand for imaging COX-1 in
human brain as a potential biomarker of neuroinflammation and for
serving as a tool in drug development. Seventeen 3-substituted 1,5-diaryl-1<i>H</i>-1,2,4-triazoles were prepared as prospective COX-1 PET
radioligands. From this set, three 1,5-(4-methoxyphenyl)-1<i>H</i>-1,2,4-triazoles, carrying a 3-methoxy (<b>5</b>),
3-(1,1,1-trifluoroethoxy) (<b>20</b>), or 3-fluoromethoxy substituent
(<b>6</b>), were selected for radioligand development, based
mainly on their high affinities and selectivities for inhibiting human
COX-1, absence of carboxyl group, moderate computed lipophilicities,
and scope for radiolabeling with carbon-11 (<i>t</i><sub>1/2</sub> = 20.4 min) or fluorine-18 (<i>t</i><sub>1/2</sub> = 109.8 min). Methods were developed for producing <b>[<sup>11</sup>C]Â5</b>, <b>[<sup>11</sup>C]Â20</b>, and [<i>d</i><sub>2</sub>-<sup>18</sup>F]<b>6</b> from hydroxy precursors
in a form ready for intravenous injection for prospective evaluation
in monkey with PET
Radiosynthesis and Evaluation of an <sup>18</sup>F-Labeled Positron Emission Tomography (PET) Radioligand for Brain Histamine Subtype-3 Receptors Based on a Nonimidazole 2-Aminoethylbenzofuran Chemotype
A known chemotype of H<sub>3</sub> receptor ligand was
explored
for development of a radioligand for imaging brain histamine subtype
3 (H<sub>3</sub>) receptors in vivo with positron emission tomography
(PET), namely nonimidazole 2-aminoethylbenzofurans, represented by
the compound (<i>R</i>)-(2-(2-(2-methylpyrrolidin-1-yl)Âethyl)Âbenzofuran-5-yl)Â(4-fluorophenyl)Âmethanone
(<b>9</b>). Compound <b>9</b> was labeled with fluorine-18
(<i>t</i><sub>1/2</sub> = 109.7 min) in high specific activity
by treating the prepared nitro analogue (<b>12</b>) with cyclotron-produced
[<sup>18</sup>F]Âfluoride ion. [<sup>18</sup>F]<b>9</b> was studied
with PET in mouse and in monkey after intravenous injection. [<sup>18</sup>F]<b>9</b> showed favorable properties as a candidate
PET radioligand, including moderately high brain uptake with a high
proportion of H<sub>3</sub> receptor-specific signal in the absence
of radiodefluorination. The nitro compound <b>12</b> was found
to have even higher H<sub>3</sub> receptor affinity, indicating the
potential of this chemotype for the development of further promising
PET radioligands