Synthesis of the first radiolabeled ¹⁸⁸Re N‐heterocyclic carbene complex and initial studies on its potential use in radiopharmaceutical applications

Abstract

A novel approach towards the synthesis of radiolabeled organometallic rhenium complexes is presented. We successfully synthesized and analyzed the first 188Re-labeled N-heterocyclic biscarbene complex, trans-dioxobis(1,1′-methylene-bis(3,3′-diisopropylimidazolium-2-ylidene))188rhenium(V) hexafluorophosphate (188Re-4) via transmetalation using an air-stable and moisture-stable silver(I) biscarbene complex. In order to assess the viability of this complex as a potential lead structure for in vivo applications, the stability of the 188Re-NHC complex was tested in physiologically relevant media. Ultimately, our studies illustrate that the complex we synthesized dissociates rapidly and is therefore unsuitable for use in radiopharmaceuticals. However, it is clear that the transmetalation approach we have developed is a rapid, robust, and mild method for the synthesis of new 188Re-labeled carbene complexes.

Cationic rhenium complexes ligated with N-heterocyclic carbenes – an overview

“…Various cationic Re(V) complexes with unsaturated mono-NHC ligands have been prepared. 4,30 Royo, Romão et al 30a and Abram et al 30b were the first to obtain cationic Re(V) oxo complexes bearing four unsaturated carbene ligands, by reacting strong Lewis basic NHCs with various rhenium precursors.…”

“…30g Based on this work, the groups of Reiner and Kühn developed a route towards a radiolabeled 188 Re N-heterocyclic carbene complex ( 188 Re-80). 4 The cold trans-dioxobis(1,1′methylene-bis(3,3′-diisopropylimidazolium-2-ylidene))rhenium(V)hexa-fluorophosphate (80) was synthesized following a previously published procedure. 4,30g By reacting ReOCl 3 (PPh 3 ) 2 with one equivalent of the corresponding silver carbene (78b) in acetonitrile, the trans-dioxorhenium biscarbene complex (80) is obtained.…”

“…The authors ascribe this to the bulkiness of the ligands at the rhenium centre and to the presence of potentially coordinating anions in the used environmental media. 4 In contrast to the similar water stable 99 Tc NHC complex (dioxobis(1,1′-methylene-bis(3,3′-dimethylimidazolium-2-ylidene))technecium(V)) published by Braband and coworkers, 40 which differs from the metal only by its less bulky methyl substituents, the bulkiness of the isopropyl ligands and the terminal oxo ligands may promote the de-coordination of the NHC ligand as the primary decomposition pathway in aqueous medium instead of reoxidation to free 188 perrhenate. The rapid decomposition in phosphate buffered saline solutions is due to the higher ionic strength of buffered solutions especially chloride anions can compete with the carbenes at the rheniumhence imidazolium salts are generated, that do not have the ability to bind to the metal again.…”

“…Despite the unfitness of this particular complex for use in radiopharmaceutical applications, due to its reduced stability under physiological conditions, a new approach for carrier-free and carrier-added radiolabeled rhenium NHC complexes has been opened. 4 These investigations done by Reiner and Kühn et al 4 illustrate that although several radiopharmaceuticals based on the Re I (CO) 3 -fragment 5o-r,41 as well as Re(V)-complexes 5h-j,l are known, only estimations based on steric, kinetic and electronic considerations can be done. Whether Re(I) or Re(V) in combination with different types of ligands are more stable under physiological relevant conditions can only be figured out by testing these compounds.…”

Bulk production and evaluation of high specific activity 186gRe for cancer therapy using enriched 186WO3 targets in a proton beam

“…A Re(V) complex, 186g ReOCl 3 (PPh 3 ) 2 , was synthesized according to a literature-reported procedure [31] and obtained with similar radiolabeling yields (60-80%). This demonstrates the utility of our high specific activity 186g ReO 4 final product for use in radiolabeling studies.…”