High Affinity and FAP-Targeted Radiotracers: A Potential Design Strategy to Improve the Pharmacokinetics and Tumor Uptake for FAP Inhibitors

  • J Med Chem. 2023 Jul 13;66(13):8614-8627. doi: 10.1021/acs.jmedchem.3c00259.
Yinwen Wang  1  2  3 ,  Hongmei Yuan  1  2  3 ,  Nan Liu  4 ,  Sufan Tang  1  2  3 ,  Yue Feng  1  2  5 ,  Yang Liu  1  2  5 ,  Ping Cai  1  2  3 ,  Li Xia  1  2  3 ,  Wenlu Zheng  1  2  5 ,  Yue Chen  1  2  5 ,  Zhijun Zhou  1  2  3  5
Affiliations
  • 1. Department of Nuclear Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China.
  • 2. Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan 646000, China.
  • 3. Department of Pharmaceutics, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan 646000, China.
  • 4. Department of Nuclear Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.
  • 5. Institute of Nuclear Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China.
PMID: 37390480 DOI: 10.1021/acs.jmedchem.3c00259
Abstract

Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts, making it an attractive target for both imaging and therapy of malignancy. This study presents a range of novel FAP inhibitors derived from amino derivatives of UAMC1110, incorporating polyethylene glycol and bulky groups containing bifunctional DOTA chelators. The compounds labeled with gallium-68 were developed and characterized to study biodistribution properties and tumor-targeting performance in nude mice bearing U87MG tumor xenografts. Several tracers of interest were screened due to the advantages in imaging and tumor-specific uptake. Positron emission tomography scans revealed that polyethylene glycol-modified 68Ga-3-3 had a rapid penetration within the neoplastic tissue and excellent tumor-to-background contrast. In a comparative biodistribution study, naphthalene-modified 68Ga-6-3 exhibited more significant tumor uptake (∼50% ID/g, 1 h p.i.) than 68Ga-3-3 and 10-fold higher than 68Ga-FAPI-04 under the same conditions. Remarkably, 68Ga-8-1, combining the two structural design strategies, obtains superior imaging performance.

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