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Published on: May 29, 2017
Development of an FAP-Targeted PET Probe Based on a Novel Quinolinium Molecular Scaffold
Lei Li1,2,3, Rui Cao4, Kaixin Chen1,2,3
1School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 201203, China.
Abstract:
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.
Insights
A novel fibroblast activation protein inhibitor (FAPI) ligand, SMIC-3002, was developed using a quinolinium scaffold. The resulting PET probe, [68Ga]Ga-SMIC-3002, shows high tumor uptake and potential for theranostic applications.
Area of Science:
- Radiopharmaceutical chemistry
- Molecular imaging
- Oncology
Background:
- Fibroblast activation protein (FAP) is a key tumor biomarker with significant diagnostic and therapeutic potential.
- Current fibroblast activation protein inhibitors (FAPI) radiotracers show promise but require further optimization for theranostics.
- Development of novel FAPI ligands is crucial for advancing cancer imaging and therapy.
Purpose of the Study:
- To design and synthesize a novel FAPI ligand, SMIC-3002, by modifying the quinoline core to a quinolinium scaffold.
- To develop and evaluate a positron emission tomography (PET) probe, [68Ga]Ga-SMIC-3002, for FAP-targeted imaging.
- To assess the in vitro and in vivo performance of [68Ga]Ga-SMIC-3002 for potential clinical translation.
Main Methods:
- Design of SMIC-3002 by altering the quinoline motif of FAPI-04 to a quinolinium scaffold.
- Radiolabeling of SMIC-3002 with Gallium-68 (68Ga) to create the PET probe [68Ga]Ga-SMIC-3002.
- In vitro stability assays and binding affinity studies (protein and cell-based).
- In vivo small animal PET/CT imaging in U87MG tumor-bearing mice to evaluate tumor uptake and biodistribution.
Main Results:
- The novel FAPI ligand SMIC-3002 was successfully synthesized with a quinolinium core.
- [68Ga]Ga-SMIC-3002 exhibited high in vitro stability and nanomolar affinity for FAP (8 nM protein, 23 nM U87MG cells).
- The PET probe demonstrated specific uptake in FAP-expressing tumors with a tumor/muscle ratio of 19.1 and tumor uptake of 1.48 ± 0.03 ID/g% at 0.5 h post-injection in mice.
Conclusions:
- The quinolinium scaffold is a viable strategy for developing novel FAP-targeted tracers.
- [68Ga]Ga-SMIC-3002 displays excellent properties for FAP-targeted PET imaging, indicating high potential for clinical theranostics.
- This study provides valuable insights for the design of next-generation FAPI radiopharmaceuticals.
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