Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

Ahmed Haider; Xiaoyun Deng; Olivia Mastromihalis; Stefanie K. Pfister; Troels E. Jeppesen; Zhiwei Xiao; Vi Pham; Shaofa Sun; Jian Rong; Chunyu Zhao; Jiahui Chen; Yinlong Li; Theresa R. Connors; April T. Davenport; James B. Daunais; Vahid Hosseini; Wenqing Ran; Arthur Christopoulos; Lu Wang; Celine Valant; Steven H. Liang

Acta Pharmaceutica Sinica B (Jan 2023)

Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

Ahmed Haider,
Xiaoyun Deng,
Olivia Mastromihalis,
Stefanie K. Pfister,
Troels E. Jeppesen,
Zhiwei Xiao,
Vi Pham,
Shaofa Sun,
Jian Rong,
Chunyu Zhao,
Jiahui Chen,
Yinlong Li,
Theresa R. Connors,
April T. Davenport,
James B. Daunais,
Vahid Hosseini,
Wenqing Ran,
Arthur Christopoulos,
Lu Wang,
Celine Valant,
Steven H. Liang

Affiliations

Ahmed Haider: Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Xiaoyun Deng: Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
Olivia Mastromihalis: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Stefanie K. Pfister: Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Troels E. Jeppesen: Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Zhiwei Xiao: Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Vi Pham: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Shaofa Sun: Hubei Collaborative Innovation Centre for Non-power Nuclear Technology, College of Nuclear Technology & Chemistry and Biology, Hubei University of Science and Technology, Xianning 437100, China
Jian Rong: Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Chunyu Zhao: Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Jiahui Chen: Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Yinlong Li: Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
Theresa R. Connors: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
April T. Davenport: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
James B. Daunais: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston Salem, NC 27157, USA
Vahid Hosseini: Terasaki Institute for Biomedical Innovation (TIBI), Los Angeles, CA 90024, USA
Wenqing Ran: Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
Arthur Christopoulos: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia
Lu Wang: Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine and PET/CT-MRI Center, the First Affiliated Hospital of Jinan University, Guangzhou 510630, China
Celine Valant: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; Corresponding authors. Tel./fax.: +1 617 230 5491.
Steven H. Liang: Department of Radiology, Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Corresponding authors. Tel./fax.: +1 617 230 5491.

Journal volume & issue: Vol. 13, no. 1
pp. 213 – 226

Abstract

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There is an accumulating body of evidence implicating the muscarinic acetylcholine receptor 4 (M4) in schizophrenia and dementia with Lewy bodies, however, a clinically validated M4 positron emission tomography (PET) radioligand is currently lacking. As such, the aim of this study was to develop a suitable M4 PET ligand that allows the non-invasive visualization of M4 in the brain. Structure–activity relationship studies of pyrazol-4-yl-pyridine derivates led to the discovery of target compound 12 ― a subtype-selective positive allosteric modulator (PAM). The radiofluorinated analogue, [18F]12, was synthesized in 28 ± 10% radiochemical yield, >37 GBq/μmol and an excellent radiochemical purity >99%. Initial in vitro autoradiograms on rodent brain sections were performed in the absence of carbachol and showed moderate specificity as well as a low selectivity of [18F]12 for the M4-rich striatum. However, in the presence of carbachol, a significant increase in tracer binding was observed in the rat striatum, which was reduced by >60% under blocking conditions, thus indicating that orthosteric ligand interaction is required for efficient binding of [18F]12 to the allosteric site. Remarkably, however, the presence of carbachol was not required for high specific binding in the non-human primate (NHP) and human striatum, and did not further improve the specificity and selectivity of [18F]12 in higher species. These results pointed towards significant species-differences and paved the way for a preliminary PET study in NHP, where peak brain uptake of [18F]12 was found in the putamen and temporal cortex. In conclusion, we report on the identification and preclinical development of the first radiofluorinated M4 PET radioligand with promising attributes. The availability of a clinically validated M4 PET radioligand harbors potential to facilitate drug development and provide a useful diagnostic tool for non-invasive imaging.

Published in Acta Pharmaceutica Sinica B

ISSN: 2211-3835 (Print); 2211-3843 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: http://www.journals.elsevier.com/acta-pharmaceutica-sinica-b

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