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 “ketamine,” “suicide,” and “depression” 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>‑Methyl-(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)­propanamide 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)­quinolin-4-yl]­oxy}­propanamide (<b>22a</b>; rat <i>K</i>_i = 0.10 nM; human TSPO genotypes <i>K</i>_i = 1.4 nM; clogD = 4.18)

2-(4-Methylsulfonylphenyl)pyrimidines as Prospective Radioligands for Imaging Cyclooxygenase-2 with PET—Synthesis, 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

3‑Substituted 1,5-Diaryl‑1<i>H</i>‑1,2,4-triazoles as Prospective PET Radioligands for Imaging Brain COX‑1 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>_1/2 = 20.4 min) or fluorine-18 (<i>t</i>_1/2 = 109.8 min). Methods were developed for producing <b>[¹¹C]­5</b>, <b>[¹¹C]­20</b>, and [<i>d</i>₂-¹⁸F]<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 ¹⁸F-Labeled Positron Emission Tomography (PET) Radioligand for Brain Histamine Subtype-3 Receptors Based on a Nonimidazole 2-Aminoethylbenzofuran Chemotype

A known chemotype of H₃ receptor ligand was explored for development of a radioligand for imaging brain histamine subtype 3 (H₃) 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)­ethyl)­benzofuran-5-yl)­(4-fluorophenyl)­methanone (<b>9</b>). Compound <b>9</b> was labeled with fluorine-18 (<i>t</i>_1/2 = 109.7 min) in high specific activity by treating the prepared nitro analogue (<b>12</b>) with cyclotron-produced [¹⁸F]­fluoride ion. [¹⁸F]<b>9</b> was studied with PET in mouse and in monkey after intravenous injection. [¹⁸F]<b>9</b> showed favorable properties as a candidate PET radioligand, including moderately high brain uptake with a high proportion of H₃ receptor-specific signal in the absence of radiodefluorination. The nitro compound <b>12</b> was found to have even higher H₃ receptor affinity, indicating the potential of this chemotype for the development of further promising PET radioligands