| Autor: |
Moon ES; Department of Chemistry-TRIGA, Johannes Gutenberg University Mainz, 55128 Mainz, Germany., Van Rymenant Y; Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium., Battan S; Department of Chemistry-TRIGA, Johannes Gutenberg University Mainz, 55128 Mainz, Germany., De Loose J; Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium., Bracke A; Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium., Van der Veken P; Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium., De Meester I; Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, 2610 Wilrijk, Belgium., Rösch F; Department of Chemistry-TRIGA, Johannes Gutenberg University Mainz, 55128 Mainz, Germany. |
| Abstrakt: |
Recently, the first squaramide-(SA) containing FAP inhibitor-derived radiotracers were introduced. DATA 5m .SA.FAPi and DOTA.SA.FAPi with their non-radioactive complexes showed high affinity and selectivity for FAP. After a successful preclinical study with [ 68 Ga]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 AAZTA 5 chelator 1,4-bis-(carboxylmethyl)-6-[bis-(carboxymethyl)-amino-6-pentanoic-acid]-perhydro-1,4-diazepine. For this molecule (AAZTA 5 .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. AAZTA 5 .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 IC 50 values for FAP and high selectivity indices over the serine proteases PREP and DPPs. Labeling with all three radiometals was easier and faster with AAZTA 5 .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 AAZTA 5 .SA.FAPi showed sufficiently high stability in different media. Therefore, these FAP inhibitor agents could be promising for theranostic approaches targeting FAP. |
