Gutenberg Open Science: Novel generation of FAP inhibitor-based homodimers for improved application in radiotheranostics

Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-8945

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DC Field	Value	Language
dc.contributor.author	Martin, Marcel	-
dc.contributor.author	Ballal, Sanjana	-
dc.contributor.author	Yadav, Madhav Prasad	-
dc.contributor.author	Bal, Chandrasekhar	-
dc.contributor.author	Van Rymenant, Yentl	-
dc.contributor.author	De Loose, Joni	-
dc.contributor.author	Verhulst, Emile	-
dc.contributor.author	De Meester, Ingrid	-
dc.contributor.author	Van Der Veken, Pieter	-
dc.contributor.author	Roesch, Frank	-
dc.date.accessioned	2023-04-03T07:37:08Z	-
dc.date.available	2023-04-03T07:37:08Z	-
dc.date.issued	2023	-
dc.identifier.uri	https://openscience.ub.uni-mainz.de/handle/20.500.12030/8961	-
dc.description.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.	en_GB
dc.language.iso	eng	de
dc.rights	CC BY	*
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/	*
dc.subject.ddc	540 Chemie	de_DE
dc.subject.ddc	540 Chemistry and allied sciences	en_GB
dc.title	Novel generation of FAP inhibitor-based homodimers for improved application in radiotheranostics	en_GB
dc.type	Zeitschriftenaufsatz	de
dc.identifier.doi	http://doi.org/10.25358/openscience-8945	-
jgu.type.contenttype	Scientific article	de
jgu.type.dinitype	article	en_GB
jgu.type.version	Published version	de
jgu.type.resource	Text	de
jgu.organisation.department	FB 09 Chemie, Pharmazie u. Geowissensch.	de
jgu.organisation.number	7950	-
jgu.organisation.name	Johannes Gutenberg-Universität Mainz	-
jgu.rights.accessrights	openAccess	-
jgu.journal.title	Cancers	de
jgu.journal.volume	15	de
jgu.journal.issue	6	de
jgu.pages.alternative	1889	de
jgu.publisher.year	2023	-
jgu.publisher.name	MDPI	de
jgu.publisher.place	Basel	de
jgu.publisher.issn	2072-6694	de
jgu.organisation.place	Mainz	-
jgu.subject.ddccode	540	de
jgu.publisher.doi	10.3390/cancers15061889	de
jgu.organisation.ror	https://ror.org/023b0x485	-
jgu.subject.dfg	Naturwissenschaften	de
Appears in collections:	DFG-491381577-G

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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

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