In Vitro Evaluation of the Squaramide-Conjugated Fibroblast Activation Protein Inhibitor-Based Agents AAZTA5.SA.FAPi and DOTA.SA.FAPi

6533b86efe1ef96bd12cb67a

RESEARCH PRODUCT

In Vitro Evaluation of the Squaramide-Conjugated Fibroblast Activation Protein Inhibitor-Based Agents AAZTA5.SA.FAPi and DOTA.SA.FAPi

Frank Rösch Yentl Van Rymenant Sandeep Battan Euy Sung Moon Ingrid De Meester An Bracke Joni De Loose Pieter Van Der Veken

subject

PREP Pharmaceutical Science Acetates Lutetium Ligands 030218 nuclear medicine & medical imaging Analytical Chemistry Serine chemistry.chemical_compound QD241-441 0302 clinical medicine Fibroblast activation protein alpha Positron Emission Tomography Computed Tomography Drug Discovery lutetium-177 AAZTA; scandium-44; lutetium-177; FAP; SA; DPP; PREP Quinine Chemistry Serine Endopeptidases Azepines scandium-44 Chemistry Chemistry (miscellaneous)030220 oncology & carcinogenesis Molecular Medicine Selectivity DPP Gallium Radioisotopes Conjugated system Article Heterocyclic Compounds 1-Ring 03 medical and health sciences SA Endopeptidases Humans DOTA Chelation Physical and Theoretical Chemistry Biology AAZTA Radioisotopes Organic Chemistry Squaramide Membrane Proteins FAP Fibroblasts Combinatorial chemistry In vitro Radiopharmaceuticals Scandium

description

Recently, the first squaramide-(SA) containing FAP inhibitor-derived radiotracers were introduced. DATA5m.SA.FAPi and DOTA.SA.FAPi with their non-radioactive complexes showed high affinity and selectivity for FAP. After a successful preclinical study with [68Ga]Ga-DOTA.SA.FAPi, the first patient studies were realized for both compounds. Here, we present a new squaramide-containing compound targeting FAP, based on the AAZTA5 chelator 1,4-bis-(carboxylmethyl)-6-[bis-(carboxymethyl)-amino-6-pentanoic-acid]-perhydro-1,4-diazepine. For this molecule (AAZTA5.SA.FAPi), complexation with radionuclides such as gallium-68, scandium-44, and lutetium-177 was investigated, and the in vitro properties of the complexes were characterized and compared with those of DOTA.SA.FAPi. AAZTA5.SA.FAPi and its derivatives labelled with non-radioactive isotopes demonstrated similar excellent inhibitory potencies compared to the previously published SA.FAPi ligands, i.e., sub-nanomolar IC50 values for FAP and high selectivity indices over the serine proteases PREP and DPPs. Labeling with all three radiometals was easier and faster with AAZTA5.SA.FAPi compared to the corresponding DOTA analogue at ambient temperature. Especially, scandium-44 labeling with the AAZTA derivative resulted in higher specific activities. Both DOTA.SA.FAPi and AAZTA5.SA.FAPi showed sufficiently high stability in different media. Therefore, these FAP inhibitor agents could be promising for theranostic approaches targeting FAP.

year	journal	country	edition	language
2021-06-01	Molecules

https://doi.org/10.3390/molecules26123482