Purification-Free Method for Preparing Technetium-99m-Labeled Multivalent Probes for Enhanced in Vivo Imaging of Saturable Systems

Abstract

Metallic radionuclides provide target-specific radiolabeled probes for molecular imaging in radiochemical yields sufficient for administration to subjects without purification. However, unlabeled ligands in the injectate can compete for targeted molecules with radiolabeled probes, which eventually necessitates postlabeling purification. Herein we describe a "1 to 3" design to circumvent the issue by taking advantage of inherent coordination properties of technetium-99m ((99m)Tc). A monovalent RGD ligand possessing an isonitrile as a coordinating moiety (CN-RGD) was reacted with [(99m)Tc(CO)3(OH2)3](+) to prepare [(99m)Tc(CO)3(CN-RGD)3](+) in over 95% radiochemical yields. This complex exhibited higher integrin αvβ3 binding affinity than its unlabeled monovalent ligand, primarily due to its multivalency. This compound visualized a murine tumor without removing unlabeled ligands, while a (99m)Tc-labeled monovalent probe derived from a monovalent ligand could not. The metal coordination-mediated synthesis of radiolabeled multivalent probes thereby can be a useful approach for preparing ready-to-use target-specific probes labeled with (99m)Tc and other metallic radionuclides of interest.

Synthesis and Evaluation of 99mTc-Tricabonyl Labeled Isonitrile Conjugates for Prostate-Specific Membrane Antigen (PSMA) Image

“…The metal center of [ 99m Tc][Tc(CO) 3 (H 2 O) 3 ] + is likewise soft and the isonitrile ligands can strongly coordinate with it in a 3:1 ratio, as reported previously [43][44][45]. Isonitrile derivatives of arginine-glycine-aspartate (RGD) and nitroimidazole were labeled with 99m Tc by inducing a reaction with [ 99m Tc][Tc(CO) 3 (H 2 O) 3 ] + and have been evaluated in vivo with promising results [38,46]. Recently, a 99m Tc-labeled tris-folate conjugate was developed by using isonitrile and [ 99m Tc][Tc(CO) 3 (H 2 O) 3 ] + to target folate receptors [47].…”

“…The [ 99m Tc][Tc(CO) 3 (H 2 O) 3 ] + has emerged as a versatile core for the labeling of biomolecules because of its excellent chelation chemistry, chemical inertness, and thermodynamic stability [35][36][37]. Furthermore, suitable mono-, bi-, and tri-dentate ligand can easily be coordinated with a [ 99m Tc] [Tc(CO) 3 (H 2 O) 3 ] + core at elevated temperature (>90 • C) by replacement of three water molecule in aqueous solution [38,39].…”

Novel 99mTc-labelled complexes with thymidine isocyanide: radiosynthesis and evaluation as potential tumor imaging tracers

“…Compound 2 was synthesized as reported previously, 35 and the isocyanide-containing active ester (compound 10) was prepared according to a previous literature report. 36 3-(3-Bromopropyl)-1-((2R,4S,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuran-2yl)-5-methylpyrimidine-2,4IJ1H,3H)-dione (3). Compound 2 (1.0 g, 2.12 mmol) and 1,3-dibromopropane (1.28 g, 3.36 mmol) were added into 10 mL DMF (N,N-dimethylformamide) (10 mL).…”

Evaluation and comparison of 99mTc‐labeled d‐glucosamine derivatives with different 99mTc cores as potential tumor imaging agents

“…[ 21 ] 99m Tc‐CN5DG exhibited a certain tumor uptake and favorable blood and muscle clearance; however, its tumor uptake needs to be increased, and its initial blood uptake needs to be decreased to obtain better SPECT images. Bearing in mind the different 99m Tc cores, lipophilicity and overall size are the main factors influencing the biodistribution results of the resulting 99m Tc complexes [ 22–26 ] ; in this study, 4‐isocyano‐ N ‐(2,4,5‐trihydroxy‐6‐(hydroxymethyl)tetrahydro‐2 H ‐pyran‐3‐yl)butanamide (CN3DG) (Scheme 1) with less methylene number was synthesized and radiolabeled with [ 99m Tc(I)] + core and [ 99m Tc(I)(CO) 3 ] + core to obtain [ 99m Tc(CN3DG) 6 ] + and [ 99m Tc(CO) 3 (CN3DG) 3 ] + (Figure 1). The feasibility of [ 99m Tc(CN3DG) 6 ] + and [ 99m Tc(CO) 3 (CN3DG) 3 ] + as tumor imaging agents were evaluated and compared in rodents in this paper.…”