Development of an FAP-Targeted PET Probe Based on a Novel Quinolinium Molecular Scaffold

• Published in: Bioconjugate chemistry 2024-09, Vol.35 (9), p.1309-1317
• Main Authors: Li, Lei, Cao, Rui, Chen, Kaixin, Qu, Chunrong, Qian, Kun, Lin, Jia, Li, Renda, Lai, Chaoquan, Wang, Xiao, Han, Zijian, Xu, Zhijian, Zhou, Liping, Song, Shaoli, Zhu, Weiliang, Cheng, Zhen
• Format: Article
• Language: English
• Subjects: Animals; Biomarkers; Cell Line, Tumor; Endopeptidases - metabolism; Fibroblast activation protein; Fibroblasts; Gallium Radioisotopes - chemistry; Humans; In vivo methods and tests; Membrane Proteins - metabolism; Mice; Mice, Nude; Pharmaceuticals; Positron emission; Positron emission tomography; Positron-Emission Tomography - methods; Precision medicine; Proteins; Quinoline; Quinolinium Compounds - chemistry; Radioisotopes; Radiopharmaceuticals - chemistry; Scaffolds; Serine Endopeptidases - metabolism; Therapeutic applications; Tissue Distribution; Tumors
• ISSN: 1043-1802; 1520-4812; 1520-4812
• DOI: 10.1021/acs.bioconjchem.4c00214

Fibroblast activation protein (FAP) has recently gained significant attention as a promising tumor biomarker for both diagnosis and therapeutic applications. A series of radiopharmaceuticals based on fibroblast activation protein inhibitors (FAPIs) have been developed and translated into the clinic. Though some of them such as radiolabeled FAPI-04 probes have achieved favorable in vivo imaging performance, further improvement is still highly desired for obtaining radiopharmaceuticals with a high theranostics potential. In this study, we innovatively designed an FAPI ligand SMIC-3002 by changing the core quinoline motif of FAPI-04 to the quinolinium scaffold. The engineered molecule was further radiolabeled with 68Ga to generate a positron emission tomography (PET) probe, [68Ga]­Ga-SMIC-3002, which was then evaluated in vitro and in vivo. [68Ga]­Ga-SMIC-3002 demonstrated high in vitro stability, nanomolar affinity for FAP (8 nM for protein, 23 nM for U87MG cells), and specific uptake in FAP-expressing tumors, with a tumor/muscle ratio of 19.1 and a tumor uptake of 1.48 ± 0.03 ID/g% at 0.5 h in U87MG tumor-bearing mice. In summary, the quinolinium scaffold can be successfully used for the development of the FAP-targeted tracer. [68Ga]­Ga-SMIC-3002 not only shows high potential for clinical translation but also offers insights into designing a new generation of FAPI tracers.