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journal article·2025-06Open access

Development of Carbon‐11 Labeled Pyrimidine Derivatives as Novel Positron Emission Tomography (PET) Agents Enabling Brain Sigma‐1 Receptor Imaging

Ping Bai, Ashley Gomm, Chi‐Hyeon Yoo, Prasenjit Mondal, Fleur Marie Lobo, Hui Meng, Yanting Zhou, Weiyao Xie, Hsiao‐Ying Wey, Rudolph E. Tanzi, Can Zhang, Changning Wang, Yu Lan

Advanced Science· Volume 12· Issue 21
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Abstract

Abstract The sigma‐1 receptor (σ1R) is a stress‐activated chaperone protein that has emerged as a significant therapeutic target for neurodegenerative disorders. Developing effective positron emission tomography (PET) imaging probes targeting σ1R is crucial for visualizing its distribution and function in the brain, as well as facilitating related drug development. In this study, two novel 11C‐labeled PET probes based on the structure of a potent σ1R ligand Lan‐0101 are designed and synthesized. PET imaging studies in mice reveal that [11C]CNY‐01 exhibits good brain uptake and binding specificity. Subsequent evaluation in non‐human primates further demonstrates that [11C]CNY‐01 displays favorable brain penetration, slow clearance kinetics, and characteristics of irreversible binding to its target in blockage experiments. To assess the clinical potential of the probe, both in vitro experiments and in vivo PET imaging using [11C]CNY‐01 are conducted in Alzheimer's disease (AD) transgenic mouse models. These studies reveal a significant decrease in σ1R expression in the brain under conditions of AD amyloid pathology and microglial activation, highlighting the probe's sensitivity to disease‐related receptor changes. This work establishes [11C]CNY‐01 as a promising tool for investigating the relationship between σ1R and neurological disorders, potentially advancing the understanding of σ1R's role in disease pathophysiology and therapeutic interventions.
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Research context

OpenAlex topics: Pharmacological Receptor Mechanisms and Effects · Receptor Mechanisms and Signaling · N-Heterocyclic Carbenes in Organic and Inorganic Chemistry

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Respiratory and Critical Care Medicine Targeted Tracer Research and Development Laboratory West China Hospital Sichuan University Chengdu Sichuan 610041 China

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

Precision Medicine Center Precision Medicine Key Laboratory of Sichuan Province West China Hospital Sichuan University Chengdu Sichuan 610041 China

The Research Units of West China Chinese Academy of Medical Sciences West China Hospital Chengdu Sichuan 610041 China

State Key Laboratory of Respiratory Health and Multimorbidity West China Hospital Chengdu Sichuan 610041 China

Genetics and Aging Research Unit McCance Center for Brain Health Mass General Institute for Neurodegenerative Disease Department of Neurology Massachusetts General Hospital Harvard Medical School 114 16th Street Charlestown MA 02129 USA

Athinoula A. Martinos Center for Biomedical Imaging Department of Radiology Massachusetts General Hospital Harvard Medical School Charlestown MA 02129 USA

Department of Pharmacy Renmin Hospital of Wuhan University Wuhan Hubei 430060 China

Funding

National Institutes of Health

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