Radiofluorination of 2-Arylquinolin-4-yl Oxypropanamide Derivatives for TSPO Imaging in Neuroinflammatory Murine, Nonhuman Primates, and Human Brain Autoradiography with Insensitivity to the rs6971 Polymorphism
The 18 kDa translocator protein (TSPO) is a critical target for PET imaging of neuroinflammation in central nervous system (CNS) disorders; however, many clinical TSPO PET tracers are limited by sensitivity to rs6971 polymorphism. In this study, three novel fluorine-containing oxypropanamide ligands were developed, with <b>11</b> (LW1, <i>K</i><sub>i</sub> = 0.07 nM) and <b>12</b> (LW2, <i>K</i><sub>i</sub> = 0.05 nM) showing high TSPO affinity. The radiolabeled [<sup>18</sup>F]<b>12</b> demonstrated superior metabolic stability, specificity, and reduced polymorphism sensitivity compared to [<sup>18</sup>F]<b>11</b> in autoradiography using Tg2576, PS19 mouse models, and human brain tissues. [<sup>18</sup>F]<b>12</b> was further evaluated in APP/PS1 transgenic mice and ischemic stroke rats for neuroinflammatory imaging and in healthy rhesus monkeys to access pharmacokinetics via dynamic PET with arterial sampling. The combination of excellent brain penetration, high specificity, and rs6971 insensitivity supports [<sup>18</sup>F]<b>12</b> as a promising TSPO PET tracer for clinical translation.
Authors
- Jiean Chen (ORCID: https://orcid.org/0000-0003-0703-5831)
- Tomoteru Yamasaki (ORCID: https://orcid.org/0000-0001-7773-3665)
- Ahmed Haider (ORCID: https://orcid.org/0000-0002-5204-4473)
- Steven H. Liang (ORCID: https://orcid.org/0000-0003-1413-6315)
- Hao Wang (ORCID: https://orcid.org/0000-0003-2169-1712)
- Ming‐Rong Zhang (ORCID: https://orcid.org/0000-0002-3001-9605)
- Bin Ji (ORCID: https://orcid.org/0000-0002-9672-6441)
- Wenqing Ran
- Xingkai Wang (ORCID: https://orcid.org/0000-0001-6943-9968)
- Zhiguo Wang (ORCID: https://orcid.org/0000-0003-1859-8728)
- Lu Wang (ORCID: https://orcid.org/0000-0002-8049-1991)
- Wakana Mori
- Shiyu Yuan (ORCID: https://orcid.org/0009-0000-2842-7354)
- Lin Xie (ORCID: https://orcid.org/0000-0002-6472-322X)
- Lingling Zhang (ORCID: https://orcid.org/0000-0002-9390-8880)
- Rui Wang (ORCID: https://orcid.org/0000-0001-5794-7201)
- Hao Lu (ORCID: https://orcid.org/0000-0002-0400-5752)
- Jinghao Wang (ORCID: https://orcid.org/0009-0006-5666-9645)
- Weijian Ye (ORCID: https://orcid.org/0000-0002-0457-3565)
- Jian Gong (ORCID: https://orcid.org/0000-0002-5643-2633)
- Hongyi Huang
- Qianqian Yang
- Kuan Hu (ORCID: https://orcid.org/0009-0004-2549-629X)
Institutions
- Emory University (US)
- Jinan University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Fudan University (CN)
- Peking Union Medical College Hospital (CN)
- Key Laboratory of Guangdong Province (CN)
- Shenzhen Bay Laboratory (CN)
- Shanghai Institute of Materia Medica (CN)
- National Institutes for Quantum Science and Technology (JP)
- Cyclotron (Netherlands) (NL)
- Metallopharm (United States) (US)
- First Affiliated Hospital of Jinan University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-06-09
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c03129
- Citations
- 2
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China
- K. C. Wong Education Foundation
- Guangzhou Science and Technology Program key projects