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

Abstract

In the synthesis of technetium-99m (Tc) labeled target-specific ligands, the presence of a large excess of unlabeled ligands over Tc in the injectate hinders target accumulation ofTc-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 Tc-labeled trivalent compound [Tc(CO)(CN-RGD)]. 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)). Tc complexation reaction, and the stability, integrin αβ binding affinity, and biodistribution of the Tc-labeled probe were investigated to evaluate the applicability of the concept to bivalent probes.Tc-[Pen-Ahx-c(RGDfK)] was obtained over 95% radiochemical yields under low Pen-Ahx-c(RGDfK) concentration (50 μM). Tc-[Pen-Ahx-c(RGDfK)] showed approximately 10-times higher integrin αβ binding affinity than the monovalent compounds, Pen-Ahx-c(RGDfK) and c(RGDyV). In biodistribution studies, the tumor accumulation of Tc-[Pen-Ahx-c(RGDfK)] was decreased to 77% and 43% of HPLC-purified (Pen-Ahx-c(RGDfK)-free) Tc-[Pen-Ahx-c(RGDfK)] by the presence of 5 nmol of unlabeled Pen-Ahx-c(RGDfK) and Re-[Pen-Ahx-c(RGDfK)], respectively. Tc-[Pen-Ahx-c(RGDfK)] provided tumor image without removing unlabeled ligand, while a Tc-labeled monovalent probe prepared from a monovalent ligand could not. These findings indicate the availability of the design concept to prepareTc-labeled bivalent probes with a variety of Tc core and other metallic radionuclides of clinical relevance.

C-terminal–modified LY2510924: a versatile scaffold for targeting C-X-C chemokine receptor type 4

“…The blockage of hepatic accumulation of 67 Ga-FRM001 by AMD3100 co-injection would facilitate the renal excretion of free 67 Ga-FRM001 in plasma, which was reflected in a slight but significant increase in the renal radioactivity levels (Table 2). Similar results were observed in radiolabeled CXCR4 probes 31,57 and a 99m Tc-labeled bivalent RGD probe 58 .…”

Zn Complex of Diaminedithiol Tetradentate Ligand as a Stable Precursor for 99mTc-Labeled Compounds

“…The RP-HPLC retention time of 99m Tc-N 2 S 2 (8.8 min) was similar to that of 185/187 Re-N 2 S 2 (8.6 min) verified by MS, IR, elemental analysis, and proton nuclear magnetic resonance ( 1 H-NMR). These results, along with previous studies [15,16], supported that the 99m Tc-N 2 S 2 would possess the chemical structure shown in Scheme 1. Figure 3 shows the results from a preliminary experiment as a function of reaction parameters.…”

“…In this study, the one-pot synthesis of 99m Tc-N 2 S 2 from Zn-N 2 S 2 was investigated at room temperature for the applications to heat-sensitive molecules. The Zn-N 2 S 2 concentration of 1.0 × 10 −5 M was selected for future applications to imaging the saturable systems of the body [16].…”

“…Since the direct reaction of 99m TcO 4 − and Zn-N 2 S 2 in the presence of a reducing agent, Sn 2+ , failed to produce 99m Tc-N 2 S 2 (Figure 3a), GH was added to the reaction mixture to stabilize the pentavalent 99m TcO 3+ against hydrolysis [16]. Under the conditions, small amounts of 99m Tc-N 2 S 2 (ca.…”

Development of a Hydroxamamide-Based Bifunctional Chelating Agent to Prepare Technetium-99m-Labeled Bivalent Ligand Probes

“…To date, several chelating groups, such as D-penicillamine 22,23 and isocyanide 24,25 , have been reported…”