Synthesis and Evaluation of [(18)F]RAGER: A First Generation Small-Molecule PET Radioligand Targeting the Receptor for Advanced Glycation Endproducts

ACS Chemical Neuroscience
Brian P CaryPeter J H Scott

Abstract

The receptor for advanced glycation endproducts (RAGE) is a 35 kDa transmembrane receptor that belongs to the immunoglobulin superfamily of cell surface molecules. Its role in Alzheimer's disease (AD) is complex, but it is thought to mediate influx of circulating amyloid-β into the brain as well as amplify Aβ-induced pathogenic responses. RAGE is therefore of considerable interest as both a diagnostic and a therapeutic target in AD. Herein we report the synthesis and preliminary preclinical evaluation of [(18)F]RAGER, the first small molecule PET radiotracer for RAGE (Kd = 15 nM). Docking studies proposed a likely binding interaction between RAGE and RAGER, [(18)F]RAGER autoradiography showed colocalization with RAGE identified by immunohistochemistry in AD brain samples, and [(18)F]RAGER microPET confirmed CNS penetration and increased uptake in areas of the brain known to express RAGE. This first generation radiotracer represents initial proof-of-concept and a promising first step toward quantifying CNS RAGE activity using PET. However, there were high levels of nonspecific [(18)F]RAGER binding in vitro, likely due to its high log P (experimental log P = 3.5), and rapid metabolism of [(18)F]RAGER in rat liver microsome studie...Continue Reading

References

Mar 3, 2004·Annals of Neurology·William E KlunkBengt Långström
May 12, 2004·Current Pharmaceutical Design·C A MathisW E Klunk
Mar 12, 2008·Current Molecular Medicine·Craig D LogsdonThiruvengadam Arumugam
Mar 20, 2008·Nuclear Medicine Communications·Arman Rahmim, Habib Zaidi
Jul 29, 2008·Brain Research·Miles C MillerEdward G Stopa
Apr 1, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·H J ChoI Mook-Jung
Nov 13, 2009·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Fang FangShirley ShiDu Yan
Dec 17, 2009·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Yared TekabeLynne L Johnson
Feb 11, 2010·Journal of Biomedicine & Biotechnology·Stephen T Buckley, Carsten Ehrhardt
May 26, 2010·Journal of Visualized Experiments : JoVE·Sagar D Joshi, Lance A Davidson
May 27, 2010·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Dean F WongMichael J Pontecorvo
Apr 5, 2011·Clinical Science·Drazenka Pongrac BarlovicKarin A M Jandeleit-Dahm
Mar 13, 2012·The Journal of Clinical Investigation·Rashid DeaneBerislav V Zlokovic
Jun 30, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Sun-Young KookInhee Mook-Jung
Jul 24, 2012·Journal of Neuroimaging : Official Journal of the American Society of Neuroimaging·Yuji SuzukiTsutomu Nakada
Feb 21, 2013·ACS Chemical Neuroscience·Stina Syvänen, Jonas Eriksson
May 3, 2013·Journal of Alzheimer's Disease : JAD·Tuan Minh DoFanchon Bourasset
May 8, 2013·Journal of Alzheimer's Disease : JAD·Vladimir KepeJorge R Barrio
Jul 11, 2013·Cellular Signalling·Jianling XieMaría Montserrat Aguilar-Hernández
Jul 13, 2013·Frontiers in Aging Neuroscience·Jens MorethKatharina Schindowski
Aug 27, 2013·Biochemical and Biophysical Research Communications·Sun-Jick KimCheol Yong Choi
Nov 26, 2013·Genome Biology and Evolution·Raquel López-DíezBegoña Aguado
Dec 12, 2013·Journal of Labelled Compounds & Radiopharmaceuticals·Jason P HollandNeil Vasdev
Jan 16, 2014·BMC Neurology·Aaron H BursteinAdnan M M Mjalli
Apr 15, 2014·European Journal of Medicinal Chemistry·Young Taek HanYoung-Ger Suh
May 16, 2014·International Journal of Molecular Imaging·Yared TekabeLynne L Johnson
Jul 19, 2014·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Robert H Mach
Dec 17, 2014·Lancet Neurology·Victor L VillemagneChristopher C Rowe
Feb 12, 2015·Journal of Medicinal Chemistry·Manuela ArizaJosé Ignacio Andrés
Feb 24, 2015·ACS Medicinal Chemistry Letters·Brian P CaryPeter J H Scott

❮ Previous
Next ❯

Citations

May 10, 2017·Journal of Medicinal Chemistry·Salvatore BongarzoneAntony D Gee
Sep 1, 2017·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Shahrzad Kharabian MasoulehA Veronica Witte
Jul 20, 2019·Journal of Huntington's Disease·Inês Caldeira BrásTiago Fleming Outeiro
Nov 23, 2017·Frontiers in Molecular Neuroscience·Xin Y ZhangLong J Zhang
Feb 16, 2017·Neural Regeneration Research·Valeria Bortolotto, Mariagrazia Grilli
Mar 14, 2020·European Journal of Nuclear Medicine and Molecular Imaging·Christian J KonopkaLawrence W Dobrucki
Aug 28, 2020·Frontiers in Aging Neuroscience·Yanyan KongYihui Guan
Nov 9, 2020·International Journal of Biological Macromolecules·D Recabarren-LeivaM Alarcón
Feb 6, 2020·ACS Chemical Neuroscience·Efthalia AngelopoulouChristina Piperi

❮ Previous
Next ❯

Related Concepts

Related Feeds

Alzheimer's Disease: Amyloid Beta

Alzheimer's disease is a neurodegenerative disease associated with the accumulation of amyloid plaques in the brain; these plaques are comprised of amyloid beta deposits. Here is the latest research in this field.

Alzheimer's Disease: APP

Amyloid precursor protein (APP) proteolysis is critical for the development of Alzheimer's disease, a neurodegenerative disease associated with accumulation of amyloid plaques in the brain. Here is the latest research on APP and Alzheimer's disease.

Alzheimer's Disease: Neuroimaging

Neuroimaging can help identify pathological hallmarks of Alzheimer's disease (AD). Here is the latest research on neuroimaging modalities, including magnetic resonance imaging and positron emission tomography, in AD.

Related Papers

Critical Care : the Official Journal of the Critical Care Forum
Marieke A D van ZoelenTom van der Poll
International Journal of Geriatric Psychiatry
M StaniszewskaA Gamian
Peritoneal Dialysis International : Journal of the International Society for Peritoneal Dialysis
M F Weiss
European Journal of Nuclear Medicine and Molecular Imaging
Guillaume BeckerLuc Zimmer
© 2022 Meta ULC. All rights reserved