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

Bioconjug Chem. 2024 Sep 18;35(9):1309-1317. doi: 10.1021/acs.bioconjchem.4c00214. Epub 2024 Jul 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Endopeptidases / metabolism
  • Gallium Radioisotopes* / chemistry
  • Humans
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Nude
  • Positron-Emission Tomography* / methods
  • Quinolinium Compounds / chemistry
  • Radiopharmaceuticals / chemistry
  • Serine Endopeptidases / metabolism
  • Tissue Distribution

Substances

  • fibroblast activation protein alpha
  • Gallium Radioisotopes
  • Radiopharmaceuticals
  • Quinolinium Compounds
  • Membrane Proteins
  • Endopeptidases
  • Serine Endopeptidases