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Article

Tailoring Fibroblast-Activation Protein Targeting for Theranostics: A Comparative Preclinical Evaluation of the 68Ga- and 177Lu-Labeled Monomeric and Dimeric Fibroblast-Activation Protein Inhibitors DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2

by
Tilman Läppchen
1,
Adrianna Bilinska
1,
Eirinaios Pilatis
1,
Elena Menéndez
1,
Surachet Imlimthan
1,
Euy Sung Moon
2,
Ali Afshar-Oromieh
1,
Frank Rösch
2,
Axel Rominger
1 and
Eleni Gourni
1,*
1
Department of Nuclear Medicine, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
2
Department of Chemistry—TRIGA Site, Johannes Gutenberg-University Mainz, 55128 Mainz, Germany
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(13), 3093; https://doi.org/10.3390/molecules29133093
Submission received: 17 May 2024 / Revised: 18 June 2024 / Accepted: 26 June 2024 / Published: 28 June 2024
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Abstract

Background: FAP radiopharmaceuticals show promise for cancer diagnosis; however, their limited tumor residency hinders treatment. This study compared two FAPi derivatives, DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2, labeled with gallium-68 and lutetium-177, aiming to determine an optimum combination for creating theranostic pairs. Methods: The radiotracers were studied for lipophilicity, binding to human serum proteins, and binding to human cancer-associated fibroblasts (CAFs) in vitro, including saturation and internalization/externalization studies. PET/SPECT/CT and biodistribution studies were conducted in PC3 and U87MG xenografts for [68Ga]Ga-DOTA.SA.FAPi and [68Ga]Ga-DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were evaluated in PC3 xenografts. Biodistribution studies of [68Ga]Ga-DOTA.SA.FAPi were performed in healthy male and female mice. Results: All radiotracers exhibited strong binding to FAP. Their internalization rate was fast while only [177Lu]Lu-DOTAGA.(SA.FAPi)2 was retained longer in CAFs. [68Ga]Ga-DOTAGA.(SA.FAPi)2 and [177Lu]Lu-DOTAGA.(SA.FAPi)2 displayed elevated lipophilicity and affinity for human serum proteins compared to [68Ga]Ga-DOTA.SA.FAPi and [177Lu]Lu-DOTA.SA.FAPi. In vivo studies revealed slower washout of [68Ga]Ga-DOTAGA.(SA.FAPi)2 within 3 h compared to [68Ga]Ga-DOTA.SA.FAPi. The tumor-to-tissue ratios of [68Ga]Ga-DOTAGA.(SA.FAPi)2 versus [68Ga]Ga-DOTA.SA.FAPi did not exhibit any significant differences. [177Lu]Lu-DOTAGA.(SA.FAPi)2 maintained a significant tumor uptake even after 96 h p.i. compared to [177Lu]Lu-DOTA.SA.FAPi. Conclusions: Dimeric compounds hold promise for therapy, while monomers are better suited for diagnostics. Finding the right combination is essential for effective disease management.
Keywords: fibroblast activation protein inhibitors (FAPi); FAPi-monomer; FAPi-dimer; gallium-68; lutetium-177 fibroblast activation protein inhibitors (FAPi); FAPi-monomer; FAPi-dimer; gallium-68; lutetium-177
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MDPI and ACS Style

Läppchen, T.; Bilinska, A.; Pilatis, E.; Menéndez, E.; Imlimthan, S.; Moon, E.S.; Afshar-Oromieh, A.; Rösch, F.; Rominger, A.; Gourni, E. Tailoring Fibroblast-Activation Protein Targeting for Theranostics: A Comparative Preclinical Evaluation of the 68Ga- and 177Lu-Labeled Monomeric and Dimeric Fibroblast-Activation Protein Inhibitors DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2. Molecules 2024, 29, 3093. https://doi.org/10.3390/molecules29133093

AMA Style

Läppchen T, Bilinska A, Pilatis E, Menéndez E, Imlimthan S, Moon ES, Afshar-Oromieh A, Rösch F, Rominger A, Gourni E. Tailoring Fibroblast-Activation Protein Targeting for Theranostics: A Comparative Preclinical Evaluation of the 68Ga- and 177Lu-Labeled Monomeric and Dimeric Fibroblast-Activation Protein Inhibitors DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2. Molecules. 2024; 29(13):3093. https://doi.org/10.3390/molecules29133093

Chicago/Turabian Style

Läppchen, Tilman, Adrianna Bilinska, Eirinaios Pilatis, Elena Menéndez, Surachet Imlimthan, Euy Sung Moon, Ali Afshar-Oromieh, Frank Rösch, Axel Rominger, and Eleni Gourni. 2024. "Tailoring Fibroblast-Activation Protein Targeting for Theranostics: A Comparative Preclinical Evaluation of the 68Ga- and 177Lu-Labeled Monomeric and Dimeric Fibroblast-Activation Protein Inhibitors DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2" Molecules 29, no. 13: 3093. https://doi.org/10.3390/molecules29133093

APA Style

Läppchen, T., Bilinska, A., Pilatis, E., Menéndez, E., Imlimthan, S., Moon, E. S., Afshar-Oromieh, A., Rösch, F., Rominger, A., & Gourni, E. (2024). Tailoring Fibroblast-Activation Protein Targeting for Theranostics: A Comparative Preclinical Evaluation of the 68Ga- and 177Lu-Labeled Monomeric and Dimeric Fibroblast-Activation Protein Inhibitors DOTA.SA.FAPi and DOTAGA.(SA.FAPi)2. Molecules, 29(13), 3093. https://doi.org/10.3390/molecules29133093

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