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Preclinical characterization of [18F]D2-LW223: an improved metabolically stable PET tracer for imaging the translocator protein 18 kDa (TSPO) in neuroinflammatory rodent models and non-human primates

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Positron emission tomography (PET) targeting translocator protein 18 kDa (TSPO) can be used for the noninvasive detection of neuroinflammation. Improved in vivo stability of a TSPO tracer is beneficial for minimizing the potential confounding effects of radiometabolites. Deuteration represents an important strategy for improving the pharmacokinetics and stability of existing drug molecules in the plasma. This study developed a novel tracer via the deuteration of [18F]LW223 and evaluated its in vivo stability and specific binding in neuroinflammatory rodent models and nonhuman primate (NHP) brains. Compared with LW223, D2-LW223 exhibited improved binding affinity to TSPO. Compared with [18F]LW223, [18F]D2-LW223 has superior physicochemical properties and favorable brain kinetics, with enhanced metabolic stability and reduced defluorination. Preclinical investigations in rodent models of LPS-induced neuroinflammation and cerebral ischemia revealed specific [18F]D2-LW223 binding to TSPO in regions affected by neuroinflammation. Two-tissue compartment model analyses provided excellent model fits and allowed the quantitative mapping of TSPO across the NHP brain. These results indicate that [18F]D2-LW223 holds significant promise for the precise quantification of TSPO expression in neuroinflammatory pathologies of the brain.

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Fig. 1: Chemical structures and radiosynthesis of TSPO ligands.
Fig. 2: Ex vivo and in vivo metabolic stability assessment.
Fig. 3: PET imaging study and biochemical analysis in LPS inflammation mouse models.
Fig. 4: PET imaging study and biochemical analysis in MCAO rat models.
Fig. 5: PET imaging and kinetic modeling of [18F]D2-LW223 conducted twice in three cynomolgus monkey brains under baseline conditions.
Fig. 6: PET-MR images and quantitative analysis in monkey brain.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (82071974, 82371998), the Guangdong Science and Technology Planning Project, China (2022A0505050042), the Science and Technology Program of Guangzhou, China (202206010106, 2023A03J0566), and the Frontier Technology Program of the First Affiliated Hospital of Jinan University, China (JNU1AF-CFTP-2022-a01214).

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  1. These authors contributed equally: Kai Liao, Jia-hui Chen.

Authors and Affiliations

  1. Center of Cyclotron and PET Radiopharmaceuticals, Department of Nuclear Medicine & Key laboratory of Basic and Translational Research on Radiopharmaceuticals, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, China

    Kai Liao, Jie Ma, Chen-chen Dong, Yuan-fang Jiang, Hui-yi Wei, Lu Hou, Jun-qi Hu, Jun-jie Wei, Chun-yuan Zeng, Hao Xu & Lu Wang

  2. Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, USA

    Jia-hui Chen, Chun-yang Bi, Ya-biao Gao, Yin-long Li & Steven H. Liang

  3. Guangdong-Hong Kong-Macau Institute of CNS Regeneration (GHMICR), Jinan University, Guangzhou, 510632, China

    Tao Wang & Sen Yan

  4. Guangzhou Key Laboratory of Basic and Translational Research on Chronic Disease, Guangzhou, 510630, China

    Lu Wang

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Contributions

Study conceptualization: HX, SHL, and LW Probe development and characterization: KL, JHC, JM, CCD, CYB, YBG, YFJ, HYW, LH, JQH, JJW, and CYZ. Data acquisition, analyses, and quality control: KL, JHC, HX, SHL, and LW. KL, JHC, TW, YLL, and SY established animal models and performed immunofluorescence staining experiments. Manuscript drafting, editing, and reviewing: KL, JHC, HX, SHL, and LW. All authors reviewed and approved the final version of this manuscript.

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Correspondence to Hao Xu, Steven H. Liang or Lu Wang.

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Liao, K., Chen, Jh., Ma, J. et al. Preclinical characterization of [18F]D2-LW223: an improved metabolically stable PET tracer for imaging the translocator protein 18 kDa (TSPO) in neuroinflammatory rodent models and non-human primates. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01375-9

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