Abstract：
:Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.
journal_name
ACS Chem Neuroscijournal_title
ACS chemical neuroscienceauthors
Fawaz MV,Brooks AF,Rodnick ME,Carpenter GM,Shao X,Desmond TJ,Sherman P,Quesada CA,Hockley BG,Kilbourn MR,Albin RL,Frey KA,Scott PJdoi
10.1021/cn500103usubject
Has Abstractpub_date
2014-08-20 00:00:00pages
718-30issue
8issn
1948-7193journal_volume
5pub_type
杂志文章abstract：:Deltorphins are naturally occurring peptides produced by the skin of the giant monkey frog (Phyllomedusa bicolor). They are δ-opioid receptor-selective agonists. Herein, we report the design and synthesis of a peptide, Tyr-d-Ala-(pI)Phe-Glu-Ile-Ile-Gly-NH2 3 (GATE3-8), based on the [d-Ala(2)]deltorphin II template, wh...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.5b00060
更新日期：2015-06-17 00:00:00
abstract：:Bipolar disorder is a complex neuropsychiatric disorder, characterized by intermittent episodes of mania and depression. Recent studies have indicated argyrophilic grains, composed of hyperphosphorylated tau, are observable in postmortem brains of bipolar patients. It remains uncertain how tau hyperphosphorylation res...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00629
更新日期：2019-03-20 00:00:00
abstract：:The nonmedical (i.e., recreational) misuse of synthetic cannabinoids (SCs) is a worldwide public health problem. When compared to cannabis, the misuse of SCs is associated with a higher incidence of serious adverse effects, suggesting the possible involvement of noncannabinoid sites of action. Here, we find that, unli...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00034
更新日期：2020-05-20 00:00:00
abstract：:The light emission chemistry of firefly luciferase can be harnessed to reveal otherwise invisible biological processes occurring in the brains of live animals. Though powerful, the need for the luciferase substrate D-luciferin to traverse the blood-brain barrier poses limitations on the sensitivity and interpretation ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.5b00195
更新日期：2015-08-19 00:00:00
abstract：:Several lines of evidence suggest the presence of severe acute respiratory coronavirus-2 (SARS-CoV-2) in wastewater. The use of sewage water for irrigation is common in many developing countries, and it is only partially treated in the majority of countries with less than 10% of collected wastewater receiving any form...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00570
更新日期：2020-10-07 00:00:00
abstract：:The present study was performed to investigate the possible role of protein kinase C (PKC) in morphine tolerance at spinal levels of rats. Intrathecal injection of 10 μg of morphine induced increases in the hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation in rats. After intrathecal inject...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn900005d
更新日期：2010-02-17 00:00:00
abstract：:Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuron loss in the substantia nigra pars compacta (SNpc). Although both iron accumulation and a defective autophagy-lysosome pathway contribute to the pathological development of PD, the connection between...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/acschemneuro.8b00390
更新日期：2019-02-20 00:00:00
abstract：:We propose a tripartite mechanism to describe the processing of cognitive information (cog-info), comprising the (1) neuron, (2) surrounding neural extracellular matrix (nECM), and (3) numerous "trace" metals distributed therein. The neuron is encased in a polyanionic nECM lattice doped with metals (>10), wherein it p...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/cn300237r
更新日期：2013-06-19 00:00:00
abstract：:The accumulation and deposition of fibrillar aggregates of α-synuclein (α-syn) into Lewy bodies are the major hallmarks of Parkinson's disease (PD) for which there is no cure yet. Disrupting preformed α-syn fibrils is considered one of the rational therapeutic strategies to combat PD. Experimental studies reported tha...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00598
更新日期：2020-12-16 00:00:00
abstract：:The sensory nervous system controls cardiovascular homeostasis via capsaicin-sensitive neurons that release calcitonin gene-related peptide (CGRP), which subsequently activates CGRP receptors. How this perivascular CGRPergic discharge is modulated, nevertheless, remains unclear. In pithed rats, systemic vasodilation i...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.9b00277
更新日期：2019-08-21 00:00:00
abstract：:Selective potentiators of glutamate response at metabotropic glutamate receptor subtype 5 (mGluR5) have exciting potential for the development of novel treatment strategies for schizophrenia. A total of 1,382 compounds with positive allosteric modulation (PAM) of the mGluR5 glutamate response were identified through h...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn9000389
更新日期：2010-04-21 00:00:00
abstract：:Genetically encoded tools are positioned to serve a unique and critical role in bridging the gap between the genetic identity of neurons and their functional properties. However, the use of these tools is limited by our current understanding of cell-type identity. As we make technological advances that focus on captur...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.5b00008
更新日期：2015-01-21 00:00:00
abstract：:Alzheimer's disease (AD) is the most common neurodegenerative disease, and its main hallmark is the deposition of amyloid beta (Aβ) peptides. However, several clinical trials focusing on Aβ-targeting agents have failed recently, and thus new therapeutic leads are focusing on alternate targets such as tau protein patho...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00114
更新日期：2020-05-20 00:00:00
abstract：:G protein-coupled receptor 55 (GPR55) is highly expressed in brain and peripheral nervous system. Originally deorphanized as a cannabinoid receptor, recently GPR55 has been described as a lysophospholipid-responsive receptor, specifically toward lysophosphatidylinositol and lysophosphatidyl-β-d-glucoside (LysoPtdGlc)....
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00505
更新日期：2019-01-16 00:00:00
abstract：:We review here recent discoveries in the exciting new field of neuromicrobiology. This field encompasses the interactions between the microbiome and the central nervous system. The microbiome has a tremendous impact on human health. In particular, the gut microbiota may play a key role in many essential processes in h...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/acschemneuro.7b00373
更新日期：2018-02-21 00:00:00
abstract：:Neurons choose growth pathways with half hearted reluctance, behavior that may be appropriate to maintain fixed long lasting connections but not to regenerate them. We now recognize that intrinsic brakes on regrowth are widely expressed in these hesitant neurons and include classical tumor suppressor molecules. Here, ...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/cn500110p
更新日期：2014-08-20 00:00:00
abstract：:Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by multiple hallmarks including extracellular amyloid (Aβ) plaques, neurofibrillary tangles, dysfunctional blood-brain barrier (BBB), neuroinflammation, and impaired autophagy. Thus, novel strategies that target multiple disease pathways wo...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.9b00175
更新日期：2019-08-21 00:00:00
abstract：:Parkinson's disease (PD) has long been seen as a disorder caused by degeneration of the dopaminergic system, leading to the classic motor manifestations of the disease. However, there is now overwhelming evidence that PD is more than a disease merely caused by dopamine depletion. It is well-known that a myriad of othe...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/acschemneuro.6b00440
更新日期：2017-05-17 00:00:00
abstract：:Natural environments contain numerous volatile compounds emanating from a large number of sources, and the survival of many animals depends on their ability to segregate odors of interest within complex odorous scenes. In a recent paper, we described how the ability of mice to detect odors within mixtures depends on t...
journal_title：ACS chemical neuroscience
pub_type： 评论,杂志文章
doi：10.1021/cn500199n
更新日期：2014-10-15 00:00:00
abstract：:The amyloid beta (Aβ) fibrillar aggregate is the hallmark of Alzheimer's disease (AD). Disassembling preformed fibril or inhibiting Aβ aggregation is considered as a therapeutic strategy for AD. Increasing evidence shows that green tea extracts, epigallocatechin-3-gallate (EGCG, containing an extra gallic acid ester g...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00277
更新日期：2020-06-17 00:00:00
abstract：:Alzheimer's disease (AD) is the most common form of dementia affecting 35 million individuals worldwide. Current AD treatments provide only brief symptomatic relief. It is therefore urgent to replace this symptomatic approach with a curative one. Increasing serotonin signaling as well as developing molecules that enha...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.5b00135
更新日期：2015-07-15 00:00:00
abstract：:Peripheral immunity is thought to be dysregulated in Parkinson's disease (PD) and may provide an avenue for novel immunotherapeutic interventions. Gut microbiota is a potential factor for modulating immunotherapy response. Considering the possibly complex role of the gut-brain axis in PD, we used a preclinical model t...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00386
更新日期：2020-10-21 00:00:00
abstract：:Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) autophosphorylation at Thr286 and Thr305/Thr306 regulates kinase activity and modulates subcellular targeting and is critical for normal synaptic plasticity and learning and memory. Here, a mass spectrometry-based approach was used to identify Ca(2+)-dependent a...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/cn500337u
更新日期：2015-04-15 00:00:00
abstract：:Brain-eating amoebae (Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri) can cause opportunistic infections involving the central nervous system. It is troubling that the mortality rate is more than 90% despite advances in antimicrobial chemotherapy over the last few decades. Here, we describe urgent k...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.7b00343
更新日期：2017-11-15 00:00:00
abstract：:The nicotinic acetylcholine receptor (nAChR) family, the archetype member of the pentameric ligand-gated ion channels, is ubiquitously distributed in the central and peripheral nervous systems, and its members are the targets for both genetic and acquired forms of neurological disorders. In the central nervous system,...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/acschemneuro.9b00041
更新日期：2019-05-15 00:00:00
abstract：:The 5-HT2C receptor has emerged as a promising target in the treatment of a variety of central nervous system disorders. We have first identified aporphines as a new class of 5-HT2C receptor agonists. Structure-activity relationship results indicate that the aporphine core may be required for 5-HT2C receptor activity,...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.9b00563
更新日期：2020-02-19 00:00:00
abstract：:Online electrochemical detection techniques are the state-of-the-art for evaluating chemical communication in the brain underlying motivated behavior and decision making. In this Viewpoint, we discuss avenues for future technological development, as well as the requirement for increasingly sophisticated and interdisci...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章,评审
doi：10.1021/cn500322y
更新日期：2015-01-21 00:00:00
abstract：:Single-cell mass spectrometry has become an established technique to study specific molecular properties such as the neuropeptide complement of identified neurons. Here, we describe a strategy to characterize, by MALDI-TOF mass spectrometry, neurochemical composition of neurons that were identified by their electrophy...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.8b00163
更新日期：2018-08-15 00:00:00
abstract：:Oligomers of amyloid β-protein (Aβ) are thought to be the proximal toxic agents initiating the neuropathologic process in Alzheimer's disease (AD). Therefore, targeting the self-assembly and oligomerization of Aβ has been an important strategy for designing AD therapeutics. In parallel, research into the metallobiolog...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.0c00192
更新日期：2020-08-05 00:00:00
abstract：:Serotonin (5-HT) is a key player in many physiological processes in both the adult organism and developing embryo. One of the mechanisms for 5-HT-mediated effects is covalent binding of 5-HT to the target proteins catalyzed by transglutaminases (serotonylation). Despite the implication in a variety of physiological pr...
journal_title：ACS chemical neuroscience
pub_type： 杂志文章
doi：10.1021/acschemneuro.9b00346
更新日期：2019-08-21 00:00:00
