Molecular Imaging of Alzheimer's Disease-Related Sigma-1 Receptor in the Brain via a Novel Ru-Mediated Aromatic 18F-deoxyfluorination Probe

Ping Bai; Frederick A Bagdasarian; Yulong Xu; Yanli Wang; Yongle Wang; Ashley Gomm; Yanting Zhou; Rui Wu; Hsiao-Ying Wey; Rudolph E Tanzi; Can Zhang; Yu Lan; Changning Wang

doi:10.1021/acs.jmedchem.3c02178

Molecular Imaging of Alzheimer's Disease-Related Sigma-1 Receptor in the Brain via a Novel Ru-Mediated Aromatic ¹⁸F-deoxyfluorination Probe

J Med Chem. 2024 Apr 25;67(8):6207-6217. doi: 10.1021/acs.jmedchem.3c02178. Epub 2024 Apr 12.

Authors

Ping Bai^{1

2

3

4

5}, Frederick A Bagdasarian⁶, Yulong Xu⁶, Yanli Wang⁶, Yongle Wang⁶, Ashley Gomm⁷, Yanting Zhou^{1

2

3

4

5}, Rui Wu^{1

2

3

4

5}, Hsiao-Ying Wey⁶, Rudolph E Tanzi⁷, Can Zhang⁷, Yu Lan⁸, Changning Wang⁶

Affiliations

¹ Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
² Institute of Respiratory Health, Targeted Tracer Research and Development Laboratory, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
³ Precision Medicine Center, Precision Medicine Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
⁴ The Research Units of West China, Chinese Academy of Medical Sciences, West China Hospital, Chengdu, Sichuan 610041, China.
⁵ State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Chengdu, Sichuan 610041, China.
⁶ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, United States.
⁷ Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, United States.
⁸ Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, China.

PMID: 38607332
DOI: 10.1021/acs.jmedchem.3c02178

Abstract

Sigma-1 receptor (σ₁R) is an intracellular protein implicated in a spectrum of neurodegenerative conditions, notably Alzheimer's disease (AD). Positron emission tomography (PET) imaging of brain σ₁R could provide a powerful tool for better understanding the underlying pathomechanism of σ₁R in AD. In this study, we successfully developed a ¹⁸F-labeled σ₁R radiotracer [¹⁸F]CNY-05 via an innovative ruthenium (Ru)-mediated ¹⁸F-deoxyfluorination method. [¹⁸F]CNY-05 exhibited preferable brain uptake, high specific binding, and slightly reversible pharmacokinetics within the PET scanning time window. PET imaging of [¹⁸F]CNY-05 in nonhuman primates (NHP) indicated brain permeability, metabolic stability, and safety. Moreover, autoradiography and PET studies of [¹⁸F]CNY-05 in the AD mouse model found a significantly decreased brain uptake compared to that in wild-type mice. Collectively, we have provided a novel ¹⁸F-radiolabeled σ₁R PET probe, which enables visualizing brain σ₁R in health and neurological diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / metabolism
Animals
Brain* / diagnostic imaging
Brain* / metabolism
Fluorine Radioisotopes* / chemistry
Halogenation
Humans
Male
Mice
Molecular Imaging / methods
Positron-Emission Tomography* / methods
Radiopharmaceuticals* / chemical synthesis
Radiopharmaceuticals* / chemistry
Radiopharmaceuticals* / pharmacokinetics
Receptors, sigma* / metabolism
Sigma-1 Receptor*
Tissue Distribution

Substances

Receptors, sigma
Sigma-1 Receptor
Fluorine Radioisotopes
Radiopharmaceuticals
Fluorine-18