Quantitative assessment of translocator protein (TSPO) in the non-human primate brain and clinical translation of [18F]LW223 as a TSPO-targeted PET radioligand

• DOI: 10.1016/j.phrs.2023.106681
• Publication Date: 2023-02-04T16:34:07Z
• Authors: Zhiqiang Tan; Achi Haider; Shaojuan Zhang; Jiahui Chen; Junjie Wei; Kai Liao; Guocong Li; Huiyi Wei; Chenchen Dong; Wenqing Ran; Ying Li; Yuefeng Li; Jian Rong; Yinlong Li; Steven H. Liang; Hao Xu; Lu Wang
• Keywords: Translocator protein; Radioligand; PET Imaging; Binding potential; Human brain; Biodistribution; Radiosynthesis; Molecular Imaging

Translocator protein 18 kDa (TSPO) positron emission tomography (PET) can be harnessed for the non-invasive detection of macrophage-driven inflammation. [18F]LW223, a newly reported TSPO PET tracer which was insensitive to rs6971 polymorphism, showed favorable performance characteristics in recent imaging study involving rat myocardial infarction model. To enable quantitative neuroimaging with we conducted kinetic analysis non-human primate (NHP) brain. Further, sought assess utility [18F]LW223-based first-in-human study. Radiosynthesis [18F]LW223 accomplished on an automated module, whereas molar activities, stability formulation, lipophilicity and unbound free fraction (fu) probe were measured. Brain penetration target specificity NHPs corroborated by PET-MR under baseline pre-blocking conditions using validated inhibitor, (R)-PK11195, at doses ranging from 5 10 mg/kg. Kinetic modeling performed one-tissue compartment model (1TCM), two-tissue (2TCM) Logan graphical analyses, dynamic data acquisition, arterial blood collection metabolic testing. Clinical scans two healthy volunteers (HVs). Regional brain standard uptake value ratio (SUVr) assessed different time intervals. synthesized non-decay corrected radiochemical yields (n.d.c. RCYs) 33.3 ± 6.5% activities 1.8 0.7 Ci/µmol (n = 11). stable formulation up 4 h LogD7.4 2.31 0.13 6) fu 5.80 1.42% determined. exhibited good NHPs, peak SUV ca. 1.79 whole Pre-treatment (R)-PK11195 substantially accelerated washout attenuated area time-activity curve, indicating vivo towards TSPO. demonstrated that 2TCM most suitable neuroimaging. Global transfer rate constants (K1) total volumes distribution (VT) found 0.10 0.01 mL/cm3/min 2.30 0.17 mL/cm3, respectively. Dynamic analyses across distinct windows revealed VT values relatively after 60 min post-injection. In preliminary clinical volunteers, considerable retention all analyzed regions. Of note, excellent correlation between SUVr obtained when assessing interval 20 40 post injection (SUVr(20–40 min), R2 0.94, p < 0.0001), suggesting this window may estimate specific binding human Our findings indicate is TSPO-targeted higher species. Employing state-of-the-art modeling, effective mapping throughout NHP brain, best fits analyses. Overall, our results exhibits species, novel tool hold promise provide neuroinflammation patients neurological disease.