PMID- 36787643
OWN - NLM
STAT- MEDLINE
DCOM- 20230224
LR  - 20230314
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Print)
IS  - 0022-2623 (Linking)
VI  - 66
IP  - 4
DP  - 2023 Feb 23
TI  - A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 
      Dysfunction in Neurodegenerative Diseases.
PG  - 2330-2346
LID - 10.1021/acs.jmedchem.2c01572 [doi]
AB  - The excitatory amino acid transporter 2 (EAAT2) plays a key role in the clearance 
      and recycling of glutamate - the major excitatory neurotransmitter in the 
      mammalian brain. EAAT2 loss/dysfunction triggers a cascade of neurodegenerative 
      events, comprising glutamatergic excitotoxicity and neuronal death. Nevertheless, 
      our current knowledge regarding EAAT2 in neurodegenerative diseases, such as 
      amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), is restricted 
      to post-mortem analysis of brain tissue and experimental models. Thus, detecting 
      EAAT2 in the living human brain might be crucial to improve diagnosis/therapy for 
      ALS and AD. This perspective article describes the role of EAAT2 in 
      physio/pathological processes and provides a structure-activity relationship of 
      EAAT2-binders, bringing two perspectives: therapy (activators) and diagnosis 
      (molecular imaging tools).
FAU - Fontana, Igor C
AU  - Fontana IC
AD  - School of Biomedical Engineering and Imaging Sciences, St Thomas' Hospital, 
      King's College London, London SE1 7EH, United Kingdom.
AD  - Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do 
      Rio Grande do Sul, Rua Ramiro Barcelos, 2600, 90035-003 Porto Alegre, Brazil.
AD  - Division of Clinical Geriatrics, Center for Alzheimer Research, Department of 
      Neurobiology, Care Sciences and Society, Karolinska Institutet, Blickagangen 16 - 
      Neo floor seventh, 141 83 Stockholm, Sweden.
FAU - Souza, Debora G
AU  - Souza DG
AUID- ORCID: 0000-0003-2982-4989
AD  - Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do 
      Rio Grande do Sul, Rua Ramiro Barcelos, 2600, 90035-003 Porto Alegre, Brazil.
AD  - Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio 
      Grande do Sul, Av. Ipiranga, 6681 Porto Alegre, Brazil.
FAU - Souza, Diogo O
AU  - Souza DO
AD  - Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do 
      Rio Grande do Sul, Rua Ramiro Barcelos, 2600, 90035-003 Porto Alegre, Brazil.
AD  - Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Rua Ramiro 
      Barcelos, 2600, 90035-003 Porto Alegre, Brazil.
FAU - Gee, Antony
AU  - Gee A
AUID- ORCID: 0000-0001-8389-9012
AD  - School of Biomedical Engineering and Imaging Sciences, St Thomas' Hospital, 
      King's College London, London SE1 7EH, United Kingdom.
FAU - Zimmer, Eduardo R
AU  - Zimmer ER
AD  - Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Rua Ramiro 
      Barcelos, 2600, 90035-003 Porto Alegre, Brazil.
AD  - Department of Pharmacology, Universidade Federal do Rio Grande do Sul, Av. 
      Sarmento Leite 500, sala, 90035-003 Porto Alegre, Brazil.
AD  - Graduate Program in Biological Sciences: Biochemistry (PPGBioq), and Pharmacology 
      and Therapeutics (PPGFT), Universidade Federal do Rio Grande do Sul, Av. Sarmento 
      Leite 500, sala, 305 Porto Alegre, Brazil.
AD  - Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio 
      Grande do Sul, Av. Ipiranga, 6681 Porto Alegre, Brazil.
AD  - McGill University Research Centre for Studies in Aging, McGill University, 
      Montreal, Quebec H4H 1R3, Canada.
FAU - Bongarzone, Salvatore
AU  - Bongarzone S
AUID- ORCID: 0000-0002-1309-3045
AD  - School of Biomedical Engineering and Imaging Sciences, St Thomas' Hospital, 
      King's College London, London SE1 7EH, United Kingdom.
LA  - eng
GR  - WT203148/Z/16/Z/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20230214
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 3KX376GY7L (Glutamic Acid)
SB  - IM
EIN - J Med Chem. 2023 Mar 23;66(6):4271. PMID: 36917065
MH  - Animals
MH  - Humans
MH  - Excitatory Amino Acid Transporter 2/metabolism
MH  - *Neurodegenerative Diseases/metabolism
MH  - *Amyotrophic Lateral Sclerosis/metabolism
MH  - Chemistry, Pharmaceutical
MH  - Brain/metabolism
MH  - Glutamic Acid/metabolism
MH  - Mammals/metabolism
PMC - PMC9969404
COIS- The authors declare the following competing financial interest(s): E.R.Z. serves 
      on the scientific advisory board of Next Innovative Therapeutics (Nintx).
EDAT- 2023/02/15 06:00
MHDA- 2023/02/25 06:00
PMCR- 2023/02/27
CRDT- 2023/02/14 17:43
PHST- 2023/02/15 06:00 [pubmed]
PHST- 2023/02/25 06:00 [medline]
PHST- 2023/02/14 17:43 [entrez]
PHST- 2023/02/27 00:00 [pmc-release]
AID - 10.1021/acs.jmedchem.2c01572 [doi]
PST - ppublish
SO  - J Med Chem. 2023 Feb 23;66(4):2330-2346. doi: 10.1021/acs.jmedchem.2c01572. Epub 
      2023 Feb 14.