Molecular Assembly of Multifunctional ^99mTc Radiopharmaceuticals Using “Clickable” Amino Acid Derivatives

Abstract

Synthetic strategies that enable the efficient and selective combination of different biologically active entities hold great promise for the development of multifunctional hybrid conjugates useful for biochemical and medical applications. Starting from side-chain-functionalized N(α)-propargyl lysine derivatives, conjugates containing a ⁹⁹(m)Tc-based imaging probe for SPECT and two different moieties (e.g., tumor-targeting vectors, pharmacological modifiers, affinity tags, or second imaging probes) can be assembled using the Cu(I)-catalyzed alkyne-azide cycloaddition in efficient one-pot protocols. This strategy was successfully applied to the preparation of a ⁹⁹(m)Tc-labeled conjugate comprising a tumor-targeting peptide sequence (bombesin(7-14)) and a low-molecular-weight albumin binder, a pharmacological modifier that prolongs the blood circulation time of the conjugate. Evaluation of the conjugate in vitro and in vivo provided promising results for its use as an imaging agent for the visualization of tumors positive for the gastrin-releasing peptide receptor. The methodology presented herein provides an attractive synthetic tool for the preparation of multifunctional ⁹⁹(m)Tc-based radiopharmaceuticals with significant potential for a multitude of applications.

Glycated 99mTc‐Tricarbonyl‐Labeled Peptide Conjugates for Tumor Targeting by “Click‐to‐Chelate”

“…The central piece of the conjugate, alkyne pro‐chelator 3 , was prepared in five steps from commercial Boc‐Lys‐OMe ( 2 ) as previously described (Scheme B) . Compound 3 was coupled via amide bond formation to d ‐glucuronic acid tetraacetate ( 5 ), which in turn was synthesized as a mixture of α/β anomers from d ‐glucuronic acid ( 4 ) according to procedures reported by Laurent et al.…”

Rhenium Complexes Based on an N2O Tridentate Click Scaffold: From Synthesis, Structural and Theoretical Characterization to a Radiolabelling Study

“…For example, several research groups, including ours, have prepared bidentate moieties based on a pyridyl‐triazole scaffold, named pyta, as alternative ligands to 2,2′‐bipyridines (Figure , molecule a ), these pyta ligands being interesting tools for the preparation of luminescent and/or bimodal imaging agents, and Rey and co‐workers have described bidentate click ligands with potential use as radiopharmaceuticals for hypoxic tissue diagnosis (Figure , molecule b ) . Concerning tridentate ligands, a variety of these systems derived from modified amino acids have been reported by Schibli and co‐workers for complexation with the 99m Tc tricarbonyl core (Figure , molecule d ) . It is noteworthy that tridentate species that include two triazolyl rings in the chelating cavity have also been described recently by Crowley and co‐workers (Figure , molecule c ) .…”

A Bombesin-Shepherdin Radioconjugate Designed for Combined Extra- and Intracellular Targeting

“…N (α)Boc- N (α)propargyl-Lys(OMe) ( 1 ) was synthesized from commercial BocLysOMe in five steps according to previously published procedures [28]. Reaction of compound 1 with succinic anhydride provided intermediate 2a appropriately functionalized with a carboxylic acid functionality for conjugation reactions via amide bond formation.…”

“…Radiolabeling of the triazole-containing peptide conjugates with 99m Tc-tricarbonyl was achieved following established procedures reported by us and others [10,28,34]. In brief, heating of aqueous solutions of 1,2,3-triazole containing peptide conjugates 12 – 16 with [ 99m Tc(CO) 3 (H 2 O) 3 ] + yielded the corresponding radiolabeled compounds [ 99m Tc(CO) 3 ( L )] ( L = 12 – 16 ) in >95% radiochemical yield and purity and with a specific activity of up to 100 GBq/µmol.…”

“…N (α)Boc- N (α)propargyl-Lys(OMe) 1 was synthesized in five steps from commercial BocLysOMe according to published procedures [28]. Subsequently, succinic anhydride (2 equiv.…”