Coordination-Mediated Synthesis of Purification-Free Bivalent 99mTc-Labeled Probes for in Vivo Imaging of Saturable System

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In the synthesis of technetium-99m ( 99m Tc) labeled target-specific ligands, the presence of a large excess of unlabeled ligands over 99m Tc in the injectate hinders target accumulation of 99m Tc-labeled ligands by competing for target molecules. To circumvent the problem, we recently developed a concept of the metal coordination-mediated multivalency, and proved the concept with a 99m Tc-labeled trivalent compound [ 99m Tc(CO) 3 (CN-RGD) 3 ] + . In this study, D-penicillamine (Pen) was selected as a chelating molecule and a cyclic RGDfK peptide was conjugated to Pen via a hexanoic linkage (Pen-Ahx-c(RGDfK)). 99m Tc complexation reaction, and the stability, integrin α v β 3 binding affinity, and biodistribution of the 99m Tc-labeled probe were investigated to evaluate the applicability of the concept to bivalent probes. 99m Tc-[Pen-Ahx-c(RGDfK)] 2 was obtained over 95% radiochemical yields under low Pen-Ahx-c(RGDfK) concentration (50 μM). 99m Tc-[Pen-Ahx-c(RGDfK)] 2 showed approximately 10-times higher integrin α v β 3 binding affinity than the monovalent compounds, Pen-Ahx-c(RGDfK) and c(RGDyV). In biodistribution studies, the tumor accumulation of 99m Tc-[Pen-Ahx-c(RGDfK)] 2 was decreased to 77% and 43% of HPLC-purified (Pen-Ahx-c(RGDfK)-free) 99m Tc-[Pen-Ahx-c(RGDfK)] 2 by the presence of 5 nmol of unlabeled Pen-Ahx-c(RGDfK) and Re-[Pen-Ahx-c(RGDfK)] 2, respectively. 99m Tc-[Pen-Ahx-c(RGDfK)] 2 provided tumor image without removing unlabeled ligand, while a 99m Tc-labeled monovalent probe prepared from a monovalent ligand could not. These findings indicate the availability of the design concept to prepare 99m Tc-labeled bivalent probes with a variety of 99m Tc core and other metallic radionuclides of clinical relevance.