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These results confirm the efficacy of ETC-216 for atherosclerosis treatment and provide guidance for dose selection and frequency to obtain a significant reduction of plaque volume.

We report the synthesis of novel chelates of Gd and (68)Ga with DPTA, DOTA, HP-DOA3, as well as with AAZTA, a novel chelating agent developed by our research group. These chelating agents were appropriately conjugated, prior to metal complexation, with DB58, an RGD peptidomimetic, conformationally constrained on an azabicycloalkane scaffold and endowed with high affinity for integrin α(ν)β(3) . Because α(ν)β(3) is involved in neo-angiogenesis in solid tumors and is also directly expressed in cancer cells (e.g. glioblastomas, melanomas) and ovarian, breast, and prostate cancers, these constructs could prove useful as molecular imaging probes in cancer diagnosis by MRI or PET techniques. Molecular modeling, integrin binding assays, and relaxivity assessments allowed the selection of compounds suitable for multiple expression on dendrimeric or nanoparticulate structures. These results also led us to an exploratory investigation of (68)Ga complexation for the promising (68)Ga-PET technique; the AAZTA complex 15((68)Ga) exhibited uptake in a xenograft model of glioblastoma, suggesting potentially useful developments with new probes with improved affinity.

The aim of this study is to describe the synthesis of, relaxometric characterization of, pharmacokinetic properties of, and animal imaging experiments with a new, low molecular weight gadolinium complex with high binding affinity toward serum albumin. The gadolinium(III) chelate (B25716/1) is based on the structure of the heptadentate ligand 1,4-bis(hydroxycarbonylmethyl)-6-[bis(hydroxycarbonylmethyl)]amino-6 methylperhydro-1,4-diazepine (AAZTA) covalently conjugated to an analogue of deoxycholic acid. The study was conducted as a comparison with that of an analogous complex based on the octadentate diethylenetriaminepentaacetic acid ligand B22956/1 (whose albumin binding properties were previously assessed). The structural modification with respect to B22956/1 leads to a system that can host two coordinated water molecules in fast exchange with bulk water with potential higher efficiency as an MRI contrast agent. On interaction with human serum albumin the expected-field-independent-relaxation enhancement is not observed, possibly as a consequence of the displacement of one of the two inner-sphere water molecules of the gadolinium complex. At clinically relevant magnetic fields, however, the plasma relaxivity of B25716/1 is markedly higher than that shown by B22956/1, owing to concomitant synergistic contributions from the electronic correlation time and water molecules in the second coordination sphere. The capability of B25716/1 to enhance tumor regions in magnetic resonance images was assessed in vivo at 3 T on a xenograft tumor mouse model prepared with PC-3 cells. B25716/1 displays signal enhancements approximately double those observed for B22956/1, in agreement with the findings of the in vitro relaxivity investigations.

The present paper describes the detection of a magnetic resonance imaging (MRI) contrast agent by matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS). The contrast agent was analyzed in both frozen and paraformaldehyde-fixed mouse livers explanted after its in vivo administration, and its identity was confirmed by fragmentation experiments. Moreover, a semiquantitative analysis was performed, evaluating its content in livers from mice sacrificed at different postadministration times. To the best of our knowledge, this is the first description of a MALDI-IMS analysis of MRI contrast agents and the first time that results obtained by MALDI-IMS are validated by both an in vivo (MRI) and an ex vivo (inductively coupled plasma atomic emission spectroscopy, ICP-AES) technique. Results shown in the present paper demonstrate the possibility of using MALDI-IMS for drug biodistribution analysis. Obviously, this application is particularly interesting in the case of unlabeled compounds, which cannot be detected by any of the other imaging techniques.