Development of a ligand for in vivo imaging of mutant huntingtin in Huntington's disease

被引：18

作者：

Bertoglio, Daniele ^{[1
]}

Bard, Jonathan ^{[2
]}

Hessmann, Manuela ^{[3
]}

Liu, Longbin ^{[2
]}

Gaertner, Annette ^{[3
]}

De Lombaerde, Stef ^{[1
,4
]}

Huscher, Britta ^{[3
]}

Zajicek, Franziska ^{[1
]}

Miranda, Alan ^{[1
]}

Peters, Finn ^{[3
]}

Herrmann, Frank ^{[3
]}

Schaertl, Sabine ^{[3
]}

Vasilkovska, Tamara ^{[5
]}

Brown, Christopher J. ^{[6
]}

Johnson, Peter D. ^{[6
]}

Prime, Michael E. ^{[6
]}

Mills, Matthew R. ^{[6
]}

Van der Linden, Annemie ^{[5
]}

Mrzljak, Ladislav ^{[2
]}

Khetarpal, Vinod ^{[2
]}

Wang, Yuchuan ^{[2
]}

Marchionini, Deanna M. ^{[2
]}

Skinbjerg, Mette ^{[2
]}

Verhaeghe, Jeroen ^{[1
]}

Dominguez, Celia ^{[2
]}

Staelens, Steven ^{[1
]}

Munoz-Sanjuan, Ignacio ^{[2
]}

机构：

[1] Univ Antwerp, Mol Imaging Ctr Antwerp Mica, B-2610 Antwerp, Belgium

[2] CHDI Management CHDI Fdn, Los Angeles, CA 90045 USA

[3] Evotec SE, D-22419 Hamburg, Germany

[4] Antwerp Univ Hosp, Dept Nucl Med, B-2650 Edegem, Belgium

[5] Univ Antwerp, Bioimaging Lab, B-2610 Antwerp, Belgium

[6] Evotec Ltd, Abingdon OX14 4RZ, Oxon, England

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2022年 / 14卷 / 630期

关键词：

TRINUCLEOTIDE REPEAT; MOUSE MODEL; PET; PROGRESSION; BINDING; GENE; DYSFUNCTION; RECEPTORS; REGION;

D O I：

10.1126/scitranslmed.abm3682

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with C-11 ([C-11]CHDI-180R) allowed noninvasive monitoring of mHTT pathology in the brain and could track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression in a rodent model. We further showed that in these animals, therapeutic agents that lowered mHTT in the striatum had a functional restorative effect that could be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.

引用

页数：13

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