[68Ga]Ga-DOTAGA-Glu(FAPi)2 Shows Enhanced Tumor Uptake and Theranostic Potential in Preclinical PET Imaging

Julie van Krimpen Mortensen; Simona Mattiussi; Lars Hvass; Emilie Graae Lund; Vladimir Shalgunov; Frank Roesch; Umberto Maria Battisti; Matthias Manfred Herth; Andreas Kjaer

doi:10.3390/diagnostics14182024

[⁶⁸Ga]Ga-DOTAGA-Glu(FAPi)₂ Shows Enhanced Tumor Uptake and Theranostic Potential in Preclinical PET Imaging

Diagnostics (Basel). 2024 Sep 13;14(18):2024. doi: 10.3390/diagnostics14182024.

Authors

Julie van Krimpen Mortensen^{1

2}, Simona Mattiussi³, Lars Hvass^{1

2}, Emilie Graae Lund^{1

2}, Vladimir Shalgunov¹, Frank Roesch⁴, Umberto Maria Battisti³, Matthias Manfred Herth^{1

3}, Andreas Kjaer^{1

2}

Affiliations

¹ Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital-Rigshospitalet, 2100 Copenhagen, Denmark.
² Cluster for Molecular Imaging, Copenhagen University Hospital-Rigshospitalet & Department of Biomedical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark.
³ Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, Denmark.
⁴ Department of Chemistry-TRIGA Site, Johannes Gutenberg University Mainz, 55128 Mainz, Germany.

Abstract

The use of fibroblast activation protein inhibitors (FAPis) for positron emission tomography (PET) imaging in cancer has garnered significant interest in recent years, yielding promising results in preclinical and clinical settings. FAP is predominantly expressed in pathological conditions such as fibrosis and cancer, making it a compelling target. An optimized approach involves using FAPi homodimers as PET tracers, which enhance tumor uptake and retention, making them more effective candidates for therapy. Here, a UAMC-1110 inhibitor-based homodimer, DOTAGA-Glu(FAPi)₂, was synthesized and radiolabeled with gallium-68, and its efficacy was evaluated in vivo for PET imaging in an endogenously FAP-expressing xenografted mouse model, U87MG. Notably, 45 min post-injection, the mean uptake of [⁶⁸Ga]Ga-DOTAGA-Glu(FAPi)₂ was 4.7 ± 0.5% ID/g in the tumor with low off-target accumulation. The ex vivo analysis of the FAP expression in the tumors confirmed the in vivo results. These findings highlight and confirm the tracer's potential for diagnostic imaging of cancer and as a theranostic companion.

Keywords: [68Ga]Ga-DOTAGA-Glu(FAPi)2; fibroblast activation protein inhibitors; gallium-68; preclinical PET imaging; theranostics.

Grants and funding

This project received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 670261 (ERC Advanced Grant) and 668532 (Click-It), the Lundbeck Foundation, the Novo Nordisk Foundation, the Innovation Fund Denmark, the Neuroendocrine Tumor Research Foundation, the Danish Cancer Society, Arvid Nilsson Foundation, the Neye. Foundation, the Sygeforsikringen danmark, the Research Foundation of Rigshospitalet, the Danish National Research Foundation (grant 126)—PERSIMUNE, the Research Council of the Capital Region of Denmark, the Danish Health Authority, the John and Birthe Meyer Foundation, and Research Council for Independent Research. Andreas Kjaer is a Lundbeck Foundation Professor. OncoProTools has received funding from the European Union’s Horizon Europe Research and Innovation programme under the Marie Skłodowska-Curie Action No 101073231.