Please use this identifier to cite or link to this item:
http://doi.org/10.25358/openscience-8945
Authors: | Martin, Marcel Ballal, Sanjana Yadav, Madhav Prasad Bal, Chandrasekhar Van Rymenant, Yentl De Loose, Joni Verhulst, Emile De Meester, Ingrid Van Der Veken, Pieter Roesch, Frank |
Title: | Novel generation of FAP inhibitor-based homodimers for improved application in radiotheranostics |
Online publication date: | 3-Apr-2023 |
Year of first publication: | 2023 |
Language: | english |
Abstract: | Radiopharmaceuticals based on the highly potent FAP inhibitor (FAPi) UAMC-1110 have shown great potential in molecular imaging, but the short tumor retention time of the monomers do not match the physical half-lives of the important therapeutic radionuclides 177Lu and 225Ac. This was improved with the dimer DOTAGA.(SA.FAPi)2, but pharmacological and radiolabeling properties still need optimization. Therefore, the novel FAPi homodimers DO3A.Glu.(FAPi)2 and DOTAGA.Glu.(FAPi)2. were synthesized and quantitatively radiolabeled with 68Ga, 90Y, 177Lu and 225Ac. The radiolabeled complexes showed high hydrophilicity and were generally stable in human serum (HS) and phosphate-buffered saline (PBS) at 37 °C over two half-lives, except for [225Ac]Ac-DOTAGA.Glu.(FAPi)2 in PBS. In vitro affinity studies resulted in subnanomolar IC50 values for FAP and high selectivity for FAP over the related proteases PREP and DPP4 for both compounds as well as for [natLu]Lu-DOTAGA.Glu.(FAPi)2. In a first proof-of-principle patient study (medullary thyroid cancer), [177Lu]Lu-DOTAGA.Glu.(FAPi)2 was compared to [177Lu]Lu-DOTAGA.(SA.FAPi)2. High uptake and long tumor retention was observed in both cases, but [177Lu]Lu-DOTAGA.Glu.(FAPi)2 significantly reduces uptake in non-target and critical organs (liver, colon). Overall, the novel FAPi homodimer DOTAGA.Glu.(FAPi)2 showed improved radiolabeling in vitro and pharmacological properties in vivo compared to DOTAGA.(SA.FAPi)2. [177Lu]Lu-DOTAGA.Glu.(FAPi)2 and [225Ac]Ac-DOTAGA.Glu.(FAPi)2 appear promising for translational application in patients. |
DDC: | 540 Chemie 540 Chemistry and allied sciences |
Institution: | Johannes Gutenberg-Universität Mainz |
Department: | FB 09 Chemie, Pharmazie u. Geowissensch. |
Place: | Mainz |
ROR: | https://ror.org/023b0x485 |
DOI: | http://doi.org/10.25358/openscience-8945 |
Version: | Published version |
Publication type: | Zeitschriftenaufsatz |
Document type specification: | Scientific article |
License: | CC BY |
Information on rights of use: | https://creativecommons.org/licenses/by/4.0/ |
Journal: | Cancers 15 6 |
Pages or article number: | 1889 |
Publisher: | MDPI |
Publisher place: | Basel |
Issue date: | 2023 |
ISSN: | 2072-6694 |
Publisher DOI: | 10.3390/cancers15061889 |
Appears in collections: | DFG-491381577-G |
Files in This Item:
File | Description | Size | Format | ||
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novel_generation_of_fap_inhib-20230323150234702.pdf | Martin, M. et al. Cancers 2023, 15(6), 1889. | 1.89 MB | Adobe PDF | View/Open | |
novel_generation_of_fap_inhib-20230323150602994.pdf | Martin, M. et al. Cancers 2023, 15(6), 1889_Supplementary Information | 1.12 MB | Adobe PDF | View/Open |