Design and Evaluation of [18F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates

被引：13

作者：

Liu, Longbin ^{[2
]}

Johnson, Peter D. ^{[1
]}

Prime, Michael E. ^{[1
]}

Khetarpal, Vinod ^{[2
]}

Brown, Christopher J. ^{[1
]}

Anzillotti, Luca ^{[3
]}

Bertoglio, Daniele ^{[4
]}

Chen, Xuemei ^{[5
]}

Coe, Samuel ^{[1
]}

Davis, Randall ^{[5
]}

Dickie, Anthony P. ^{[1
]}

Esposito, Simone ^{[3
]}

Gadouleau, Elise ^{[1
]}

Giles, Paul R. ^{[1
]}

Greenaway, Catherine ^{[1
]}

Haber, James ^{[5
]}

Halldin, Christer ^{[6
]}

Haller, Scott ^{[7
]}

Hayes, Sarah ^{[1
]}

Herbst, Todd ^{[2
]}

Herrmann, Frank ^{[8
]}

Hessmann, Manuela ^{[8
]}

Hsai, Ming Min ^{[5
]}

Khani, Yaser ^{[6
]}

Kotey, Adrian ^{[1
]}

Lembo, Angelo ^{[3
]}

Mangette, John E. ^{[5
]}

Marriner, Gwendolyn A. ^{[7
]}

Marston, Richard W. ^{[1
]}

Mills, Matthew R. ^{[1
]}

Monteagudo, Edith ^{[2
]}

Forsberg-Moren, Anton ^{[6
]}

Nag, Sangram ^{[6
]}

Orsatti, Laura ^{[3
]}

Sandiego, Christine ^{[9
]}

Schaertl, Sabine ^{[8
]}

Sproston, Joanne ^{[1
]}

Staelens, Steven ^{[4
]}

Tookey, Jack ^{[1
]}

Turner, Penelope A. ^{[1
]}

Vecchi, Andrea ^{[3
]}

Veneziano, Maria ^{[3
]}

Munoz-Sanjuan, Ignacio ^{[2
]}

Bard, Jonathan ^{[2
]}

Dominguez, Celia ^{[2
]}

机构：

[1] Evotec UK Ltd, Abingdon OX14 4RZ, Oxon, England

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

[3] IRBM SpA, Expt Pharmacol Dept, I-00071 Rome, Italy

[4] Univ Antwerp, Mol Imaging Ctr Antwerp MICA, B-2610 Antwerp, Belgium

[5] Curia Global Inc, Buffalo, NY 14203 USA

[6] Karolinska Inst, Ctr Psychiat Res, Karolinska Hosp, Dept Clin Neurosci, S-17176 Stockholm, Sweden

[7] Charles River Labs, Mattawan, MI 49071 USA

[8] Evotec SE, Manfred Eigen Campus, D-22419 Hamburg, Germany

[9] Invicro, New Haven, CT 06510 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2023年 / 66卷 / 01期

关键词：

5-HT1A RECEPTORS; DRUG; DEFLUORINATION; F-18-FCWAY; DISCOVERY; BINDING; F-18;

D O I：

10.1021/acs.jmedchem.2c01585

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients. The major in vivo metabolic pathway via aldehyde oxidase was blocked with a 2-methyl group on the pyrimidine ring. A strategically placed ring-nitrogen on the benzoxazole core ensured high free fraction in the brain without introducing efflux. Replacing a methoxy pendant with a fluoro-ethoxy group and introducing deuterium atoms suppressed oxidative defluorination and accumulation of [18F]-signal in bones. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing.

引用

页码：641 / 656

页数：16

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