Characterization of a novel PET radioligand for mitochondrial complex I in nonhuman primate

Yulong Xu; Yiming Xu; Frederick Andrew Bagdasarian; Tewodros Mulugeta Dagnew; Hua Cheng; Yanli Wang; Yongle Wang; Leyi Kang; Hsiao-Ying Wey; Can Zhang; Shijun Zhang; Changning Wang

doi:10.1016/j.nucmedbio.2025.108993

Characterization of a novel PET radioligand for mitochondrial complex I in nonhuman primate

Nucl Med Biol. 2025 Jan 10:142-143:108993. doi: 10.1016/j.nucmedbio.2025.108993. Online ahead of print.

Authors

Affiliations

¹ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States.
² Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, United States.
³ Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States.
⁴ Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, United States. Electronic address: [email protected].
⁵ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, United States. Electronic address: [email protected].

PMID: 39824008
DOI: 10.1016/j.nucmedbio.2025.108993

Abstract

The role of mitochondrial complex I (MC-I) dysfunction is well-documented across a range of neurodegenerative disorders. Recently, a novel positron emission tomography (PET) radioligand, [¹⁸F]CNL02, has been synthesized to target MC-I. In this paper, we provide a comprehensive characterization of [¹⁸F]CNL02, using nonhuman primate as a model system. In the brain of a rhesus macaque, [¹⁸F]CNL02 demonstrated specific binding in regions expressing MC-I. All observed brain regions showed rapid kinetic profiles. Analysis of arterial plasma indicated a swift clearance of [¹⁸F]CNL02 from the bloodstream. Metabolite analysis identified two predominant radiometabolites in the plasma. The regional brain time-activity curves (TACs) for [¹⁸F]CNL02 were effectively characterized through a two-tissue compartment model (2TCM). Furthermore, the total distribution volume was reliably estimated employing the Logan plot method. Consequently, continued development and refinement of [¹⁸F]CNL02 are imperative.

Keywords: Brain tissue; Mitochondrial complex I; Positron emission tomography; Radiotracers; Rhesus macaque.