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 (188)Re-labeled N-heterocyclic biscarbene complex, trans-dioxobis(1,1'-methylene-bis(3,3'-diisopropylimidazolium-2-ylidene))(188)rhenium(V) hexafluorophosphate ((188)Re-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 (188)Re-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 (188)Re-labeled carbene complexes.

Keywords: 188Re carbene complex; N-heterocyclic carbene; radiopharmaceutical application; transmetalation.

Figure 1

General design of ^186/188Re tracers that already have been used in clinical applications: (A) N2S2-type amine/amidodithiolato ligand on an oxorhenium(V) core. (B) NS3-type combination of amidodithiolate and thiolato ligands on an oxorhenium(V) core. (C) DMSA or DMSA derivatives as stabilizing ligand for oxorhenium(V) cores. (D) Oxorhenium(V) core with an N3S-type or MAG3 ligand, used for coupling to biomacromolecules. (E) Rhenium(I)tricarbonyl core structure with three-coordinate bifunctional ligands, mostly used for coupling biomacromolecules. (F) Schematic drawing of a rhenium/sulfur colloid used, for example, in radio-synovectomies.

Figure 2

Synthesis and identification of cold dioxobis(1,1′-methylene-bis(3,3′-diisopropylimidazolium-2-ylidene))rhenium(V) hexafluorophosphate, 4. (A) Reaction scheme for the transmetalation reaction to yield compound 4. (B) Mass spectrometry of compound 4. (C) High-resolution mass spectrometry, displaying the exact mass and the isotopic pattern of 4 and its protonated, dicationic form. (D) UV-spectrum of compound 4 with a strong absorption band at 310 nm.

Figure 3

Synthesis of trans-dioxobis(1,1′-methylene-bis(3,3′-diisopropylimidazolium-2-ylidene))¹⁸⁸rhenium(V) hexafluorophosphate, ¹⁸⁸Re-4. (A) Reaction scheme of the synthesis of compound ¹⁸⁸Re-4. (B) UV and (C) radio HPLC signal of a purified sample of compound ¹⁸⁸Re-4.

Figure 4

Yields, specific activities, and stability of ¹⁸⁸Re-4 in aqueous solution. (A) Effect of added cold carrier ReOCl₃(PPh₃)₂ on the yield of compound ¹⁸⁸Re-4. (B) Specific activity of ¹⁸⁸Re-4 at different amounts of added cold carrier. (C) Stability of ¹⁸⁸Re-4 in H2O at different pH values over time. Peak areas are normalized to the initial amount of ¹⁸⁸Re-4.

Figure 5

Stability of ¹⁸⁸Re-4. Radio-HPLC of ¹⁸⁸Re-4 in H2O (A), PBS (B), and FBS (C) after incubation at 37 °C for 1, 2, 3, and 4 h, respectively. Green arrow: ¹⁸⁸Re-4; Red arrow: ¹⁸⁸ReO4^-.