Translational assessment of a DATA-functionalized FAP inhibitor with facile 68Ga-labeling at room temperature.

PURPOSE: The present study aims at evaluating the preclinical and the clinical performance of [68Ga]Ga-DATA5m.SA.FAPi, which has the advantage to be labeled with gallium-68 at room temperature. METHODS: [68Ga]Ga-DATA5m.SA.FAPi was assessed in vitro on FAP-expressing stromal cells, followed by biodistribution and in vivo imaging on prostate and glioblastoma xenografts. Moreover, the clinical assessment of [68Ga]Ga-DATA5m.SA.FAPi was conducted on six patients with prostate cancer, aiming on investigating, biodistribution, biokinetics, and determining tumor uptake. RESULTS: [68Ga]Ga-DATA5m.SA.FAPi is quantitatively prepared in an instant kit-type version at room temperature. It demonstrated high stability in human serum, affinity for FAP in the low nanomolar range, and high internalization rate when associated with CAFs. Biodistribution and PET studies in prostate and glioblastoma xenografts revealed high and specific tumor uptake. Elimination of the radiotracer mainly occurred through the urinary tract. The clinical data are in accordance with the preclinical data concerning the organ receiving the highest absorbed dose (urinary bladder wall, heart wall, spleen, and kidneys). Different to the small-animal data, uptake of [68Ga]Ga-DATA5m.SA.FAPi in tumor lesions is rapid and stable and tumor-to-organ and tumor-to-blood uptake ratios are high. CONCLUSION: The radiochemical, preclinical, and clinical data obtained in this study strongly support further development of [68Ga]Ga-DATA5m.SA.FAPi as a diagnostic tool for FAP imaging.

Radiochemical and radiobiological assessment of a pyridyl-S-cysteine functionalized bombesin derivative labeled with the (99m)Tc(CO)3(+) core.

Bombesin is a neuropeptide widely studied due to its ability to target various types of cancers. Technetium-99m on the other hand is ideal for diagnostic tumor targeting. The aim of the present study is the investigation of the coupling of the ligand (S)-(2-(2'-pyridyl)ethyl)-d,l-cysteine with the BN-peptide Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met(CONH2) through the spacer aminohexanoic acidand the labeling of the resulting derivative MBN with the synthon [M(CO)3(H2O)3](+) (M=(99m)Tc, Re). The peptide was synthesized according to the SPPS method, purified and characterized by ESI-MS. The new (99m)Tc-labeled biomolecule was stable in vitro, showed high affinity for the human GRP receptor expressed in PC3 cells and the rate of internalization was found to be time-dependent tissue distribution of the radiopeptide was evaluated in normal mice and in prostate cancer experimental models and significant radioactivity uptake was observed in the pancreas of normal mice as well as in PC3 tumors. Dynamic studies of the radiopeptide showed satisfactory tumor images.

Synthesis and comparative assessment of a labeled RGD peptide bearing two different 99mTc-tricarbonyl chelators for potential use as targeted radiopharmaceutical.

During the past decade radiolabeled RGD-peptides have been extensively studied to develop site-directed targeting vectors for integrins. Integrins are heterodimeric cell-surface adhesion receptors, which are upregulated in cancer cells and neovasculature during tumor angiogenesis and recognize the RGD aminoacid sequence. In the present study, we report the synthesis and development of two derivatives of the Nε-Lys derivatized cyclic Arg-Gly-Asp-D-Phe-Lys peptide, namely of cRGDfKHis and cRGDfK-CPA (CPA: 3-L-Cysteine Propionic Acid), radiolabeled via the [(99m)Tc(H(2)O)(3)(CO)(3)](+) metal aquaion at a high yield even at low concentrations of 10-5M (>87%) for cRGDfK-10-5M (>93%) for cRGDfK-CPA. Radiolabeled peptides were characterized with regard to their stability in saline, in His/Cys solutions, as well as in plasma, serum and tissue homogenates and were found to be practically stable. Internalization and efflux assays using αvß3-receptor-positive MDA-MB 435 breast cancer cells showed a good percentage of quick internalization (29.1 ± 9.8% for (99m)Tc-HiscRGDfK and 37.0 ± 0.7% for (99m)Tc-CPA-cRGDfK at 15 min) and no retention of radioactivity for both derivatives. Their in vivo behavior was assessed in normal mice and pathological SCID mice bearing MDA-MB 435 ανß3 positive breast tumors. Both presented fast blood clearance and elimination via both the urinary and hepatobiliary systems, with (99m)Tc-His-cRGDfK remaining for a longer time than (99m)Tc-CPA-cRGDfK in all organs examined. Tumor uptake 30 min pi was higher for (99m)Tc-CPAcRGDfK (4.2 ± 1.5% ID/g) than for (99m)Tc-His-cRGDfK (2.8 ± 1.5% ID/g). Dynamic scintigraphic studies showed that the tumor could be visualized better between 15 and 45 min pi for both radiolabeled compounds but low delineation occurred due to high abdominal background. It was finally noticed that the accumulated activity on the tumor site was depended on the size of the experimental tumor; the smaller the size, the higher was the radioactivity concentration.

Structural assessment and biological evaluation of two N3S bombesin derivatives.

The aim of the present study is the evaluation of the (99m)Tc complexes of two bombesin-like peptides: Gly1'-Gly2'-Cys3'-Aca-BN[2-14] (BN-1.1) and Gly1'-Gly2'-Cys3'-Aca-BN[7-14] (BN-1.1p). The BN derivatives were synthesized according to the solid phase peptide synthesis method, and characterized by ESI-MS and NMR. (185/187)Re-BN-1.1 and (185/187)Re-BN-1.1p were also identified by ESI-MS and NMR. The (99m)Tc complexes were stable over time in human plasma, while they degraded rapidly in kidney-liver homogenates. The peptides and their (99m)Tc complexes showed high affinity for the human GRP receptors expressed in PC-3 cells. The rate of internalization of these radiolabeled biomolecules was found to be time-dependent. Also, it was found that there was no long-term retention of the radioactive metabolites into the cells. Tissue distribution of the radiopeptides was evaluated in normal mice and in prostate cancer experimental models. Significant uptake of radioactivity was observed in the pancreas of PC-3 tumor-bearing SCID mice. Dynamic studies of both radiopeptides showed satisfactory tumor images.