Abstract：
:Phosphodiesterase 7B (PDE7B) inhibition has been considered as a therapeutic target for the treatment of several neurological disorders. Currently, there are no radio-labeled tracers available to determine receptor occupancy (RO) of this target. Developing such a tracer could greatly facilitate the identification of viable PDE7B inhibitors. In the current study, a liquid chromatography tandem mass spectrometry (LC─MS/MS) method was utilized to evaluate the brain distribution of unlabeled tracer candidates following intravenous micro-dosing. This novel approach resulted in an accelerated identification of a potential novel RO tracer for PDE7B. The identified molecule, Compound 30, showed reasonable target-tissue specificity (striatum/cerebellum ratio of 2.2) and suitable uptake (0.25% of the injected dose/g brain tissue) as demonstrated in rats dosed with the unlabeled compound. Compound 30 was subsequently labeled with tritium (3H). In vitro characterization of 3H-Compound 30 demonstrated that this compound possessed a high target affinity with a subnanomolar Kd (0.8 nM) and a Bmax of 58 fmol/mg of protein using rat brain homogenate. Intravenous microdosing of 3H-Compound 30 showed preferential binding in the rat striatum, consistent with the mRNA distribution of PDE7B. In vitro displacement study with other structurally distinct PDE7B target-specific inhibitors using rat brain homogenate indicated that 3H-Compound 30 is an ideal tracer for Ki analysis. This is the first report of a preclinical tracer for PDE7B. With further characterization, Compound 30 may ultimately show the appropriate properties required to be further developed as a PDE7B PET ligand for clinical studies.
journal_name
Neurochem Intjournal_title
Neurochemistry internationalauthors
Chen J,Gu G,Chen M,Scott T,Heger L,Zook D,Chung D,Keenan T,Renick J,Santora VJ,Vivian J,Stauber K,Breitenbucher JG,Tabatabaei Adoi
10.1016/j.neuint.2020.104735subject
Has Abstractpub_date
2020-07-01 00:00:00pages
104735eissn
0197-0186issn
1872-9754pii
S0197-0186(20)30126-1journal_volume
137pub_type
杂志文章abstract：:High-affinity binding sites for tritiated hemicholinium-3, a potent and selective inhibitor of the sodium-dependent high-affinity choline transport, have been found in synaptosomal membranes from insect ganglia. The binding of hemicholinium to ganglionic membrane preparations was saturable and specific with an apparen...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/0197-0186(89)90124-1
更新日期：1989-01-01 00:00:00
abstract：:Excessive glucocorticoid levels in depressed patients have been associated with atrophic changes in some brain regions, but only few studies suggest that some antidepressants can interfere with deleterious effect of glucocorticoids on neuronal cells. The aim of the present study was to examine the effect of dexamethas...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2013.07.007
更新日期：2013-11-01 00:00:00
abstract：:The presence of nicotinic and muscarinic receptors suggests the occurrence of cholinergic neurotransmission in white matter; however no quantitative information exists on acetylcholine formation and breakdown in white matter. We compared white structures of pig brain (fimbria, corpus callosum, pyramidal tracts, and oc...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2008.06.008
更新日期：2008-12-01 00:00:00
abstract：:Ischemic neuronal injury is associated with several life- and vision-threatening diseases. Neuroprotection is essential in the treatment of these diseases. Here, we identified and characterized a novel peptide, FK18, from basic fibroblast growth factor (bFGF). We further assessed the neuroprotective effects of this pe...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2017.02.015
更新日期：2017-09-01 00:00:00
abstract：:Antibodies to electrolectin, a lectin endogenous to embryonic skeletal muscle, have been used to study the distribution of lectin during myogenesis in L(6) cells by using immunohistofluorescence microscopy. Evidence for both surface and cytoplasmic forms of lectin is presented. Cytoplasmic lectin does not appear to be...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/0197-0186(80)90041-8
更新日期：1980-01-01 00:00:00
abstract：:Gliomas are the most common and malignant primary brain tumours and are associated with a poor prognosis despite the availability of multiple therapeutic options. Quercetin, a traditional Chinese medicinal herb, is an important flavonoid and has anti-cancer activity. Here, we evaluated whether quercetin could inhibit ...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2014.12.001
更新日期：2015-01-01 00:00:00
abstract：:Biochemical abnormalities have been implicated in possible mechanisms underlying the epileptic phenomena. Some of these alterations include changes in the activity of several enzymes present in epileptic tissues. Systemic administration of pilocarpine in rats induces electrographic and behavioral limbic seizures and s...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/0197-0186(95)00153-0
更新日期：1996-05-01 00:00:00
abstract：:Human atrial natriuretic peptide (Ser 99-Tyr 126) was rapidly degraded by both choroid plexus and hypothalamic membranes with a complex pattern of cleavage. The use of protease inhibitors allowed a preliminary characterization of the enzymes involved in the hydrolysis of the Ser-Phe and Phe-Arg bonds of iodine-labelle...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/0197-0186(88)90176-3
更新日期：1988-01-01 00:00:00
abstract：:Increased noradrenaline, induced by rapid eye movement (REM) sleep deprivation, stimulates Na-K ATPase activity in the rat brain. The brain contains neurons as well as glia and both possess Na-K ATPase, however, it was not known if REM sleep deprivation affects the enzyme in both types of cells identically. Rats were ...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2008.10.006
更新日期：2009-01-01 00:00:00
abstract：:The opening of pannexin-1 (Px1) hemichannels is regulated by the activity of P2X(7) receptors (P2X(7)Rs). At present, however, little is known about how extracellular ATP-sensitive P2X(7)Rs regulates the opening and closure of Px1 hemichannels. Several lines of evidence suggest that P2X(7)Rs are activated under pathol...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2010.12.013
更新日期：2011-02-01 00:00:00
abstract：:Excitotoxicity is the main event during neurological disorders producing drastic morphological and functional changes. Rac-GTPase is involved in cytoskeletal remodeling and survival. However, the role of Rac1 after cerebral ischemia has not been completely understood yet. In this study, we evaluated the activity of Ra...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2010.08.014
更新日期：2010-12-01 00:00:00
abstract：:Previously we have demonstrated the presence of presynaptic nicotinic acetylcholine receptors on the terminals of myenteric neurons in Auerbach's plexus of guinea-pig ileum. During these studies we observed, that the presence of hemicholinium-3, an inhibitor of the high affinity choline uptake significantly influences...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2006.03.001
更新日期：2006-09-01 00:00:00
abstract：:Aging is a biological process characterized by impairment of cellular bioenergetic function, increased oxidative stress, attenuated ability to respond to stresses, increased risk of contracting age-associated disorders that affects many tissues, with a more marked effect on brain and heart function. Oxidative stress i...
journal_title：Neurochemistry international
pub_type： 杂志文章,评审
doi：10.1016/j.neuint.2010.12.016
更新日期：2011-03-01 00:00:00
abstract：:The immunostains of GD3, c-pathway polysialogangliosides and gangliotetraosylgangliosides belonging to the a- and b-pathways were analyzed in embryo optic lobe cells. Cells were cultured in serum free media with, and without, bovine brain ganglioside mixture (largely gangliotetraosylgangliosides). Control cells differ...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/0197-0186(94)90110-4
更新日期：1994-04-01 00:00:00
abstract：:A novel copper-containing protein has been isolated in electrophoretically homogeneous state from bovine brain extracts. Some physico-chemical properties of the protein are determined (molecular weight, copper content, isoelectric point, amino acid composition, optical and EPR spectra), and they are compared with thos...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/0197-0186(88)90071-x
更新日期：1988-01-01 00:00:00
abstract：:Selective dopaminergic neurotoxicity induced by 1-methyl-4-phenylpyridine (MPP+) is believed to be due to the transmembrane uptake by the dopamine transporter and subsequent inhibition of mitochondrial complex I and/or production of free radicals. However, little is known about the molecular sequence of intracellular ...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/s0197-0186(99)00083-2
更新日期：1999-11-01 00:00:00
abstract：:Long-term potentiation (LTP) is a well-established experimental model used to investigate the synaptic basis of learning and memory. LTP at mossy fibre - CA3 synapses in the hippocampus is unusual because it is normally N-methyl-d-aspartate (NMDA) receptor-independent. Instead it seems that the trigger for mossy fibre...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2012.04.021
更新日期：2012-09-01 00:00:00
abstract：:Vasogenic mechanism of brain edema in acute liver failure (ALF) remains poorly understood. Recent work demonstrates that matrix metalloproteinase-9 (MMP-9) contributes to the development of brain edema in experimental ALF (J Hepatol 44:1105, 2006). Importantly, MMP-9 blockage with specific monoclonal antibodies and/or...
journal_title：Neurochemistry international
pub_type： 评论,信件
doi：10.1016/j.neuint.2009.07.013
更新日期：2010-01-01 00:00:00
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journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2008.12.013
更新日期：2009-05-01 00:00:00
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journal_title：Neurochemistry international
pub_type： 杂志文章,评审
doi：10.1016/s0197-0186(02)00045-1
更新日期：2002-11-01 00:00:00
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journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2010.03.019
更新日期：2010-11-01 00:00:00
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journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2021.104961
更新日期：2021-01-16 00:00:00
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journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/0197-0186(86)90004-5
更新日期：1986-01-01 00:00:00
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journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/s0197-0186(97)00020-x
更新日期：1997-10-01 00:00:00
abstract：:Recent studies suggest that the behavioral effects of chronic antidepressant treatment are mediated by stimulation of hippocampal neuronal plasticity and neurogenesis. The present study was designed to examine the effects of 3,6'-disinapoyl sucrose (DISS), a bioactive component of Polygala tenuifolia Willd, on the exp...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2009.12.004
更新日期：2010-02-01 00:00:00
abstract：:Human glutamate dehydrogenase (GDH) gene was fused with a gene fragment encoding the nine amino acid (RKKRRQRRR) protein transduction domain of human immunodeficiency virus TAT protein in bacterial expression vector to produce genetic in-frame TAT-GDH fusion protein. The TAT-GDH protein can enter PC12 cells efficientl...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/s0197-0186(01)00138-3
更新日期：2002-07-01 00:00:00
abstract：:Differentiating granule cells develop survival requirements in vitro which can be met by treatment with high K+ or excitatory amino acids. Promotion of cell survival by N-methyl-D-aspartate (NMDA) or kainate has already been established and here we report that treatment of the cells with alpha-amino-3-hydroxy-5-methyl...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/0197-0186(94)90067-1
更新日期：1994-09-01 00:00:00
abstract：:The amyloid beta-peptide (AbetaP) is the major protein component of brain senile plaques in Alzheimer's disease. The redox state of methionine-35 residue plays a critical role in peptide neurotoxic actions. We used the fragment 31-35 of AbetaP [AbetaP(31-35)], containing a single methionine-35 residue (Met-35), to inv...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2006.03.014
更新日期：2006-10-01 00:00:00
abstract：:Hydrogen sulfide (H(2)S) is a novel neurotransmitter. We studied here the effect of ACS 84, a new H(2)S releasing compound, on the cytotoxicity induced by amyloid beta (Aβ) in microglia. Treatment with Aβ(1-40) (25μmol/L) for 24h significantly inhibited MTT reduction and increased lactate dehydrogenase release in BV-2...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/j.neuint.2011.01.023
更新日期：2011-04-01 00:00:00
abstract：:The cholinergic nerve terminals of Torpedo electric organ are a rich source of a hydrophobic protein, the mediatophore, which endows artificial membranes with a calcium dependent mechanism that translocates acetylcholine. An antiserum raised against purified mediatophore permitted the identification of two different p...
journal_title：Neurochemistry international
pub_type： 杂志文章
doi：10.1016/0197-0186(89)90097-1
更新日期：1989-01-01 00:00:00
