Radiolabelled Cyclic Bisarylmercury: High Chemical and in vivo Stability for Theranostics

Abstract

We show the synthesis of an in vivo stable mercury compound with functionality suitable for radiopharmaceuticals. The designed cyclic bisarylmercury was based on the water tolerance of organomercurials, higher bond dissociation energy of HgÀ Ph to HgÀ S, and the experimental evidence that acyclic structures suffer significant cleavage of one of the HgÀ R bonds. The bispidine motif was chosen for its in vivo stability, chemical accessibility, and functionalization properties. Radionuclide production results in 197(m) HgCl 2 (aq), so the desired mercury compound was formed via a water-tolerant organotin transmetallation. The Hg-bispidine compound showed high chemical stability in tests with an excess of sulfur-containing competitors and high in vivo stability, without any observable protein interaction by human serum assay, and good organ clearance demonstrated by biodistribution and SPECT studies in rats. In particular, no retention in the kidneys was observed, typical of unstable mercury compounds. The nat Hg analogue allowed full characterization by NMR and HRMS.

Selective Chelation of the Exotic Meitner‐Auger Emitter Mercury‐197 m/g with Sulfur‐Rich Macrocyclic Ligands: Towards the Future of Theranostic Radiopharmaceuticals

“…Structure of A) chlormerodrin, [19][20][21] B) and C) 197m/g Hg organometallic compounds developed for radiopharmaceuticals incorporation by Gilpin et al and Pietzsch et al [25,26] D) bifunctional trithiamacrocycle reported by Blower et al [27] Chemistry-A European Journal…”

“…To the best of our knowledge, this is the first example of a chelator capable of yielding high radiomercury incorporation in a stable complex under biocompatible conditions (pH 7 and 37 °C), enabling the future use of a plethora of targeting vectors including temperature-sensitive biomolecules (i. e. antibodies). [25,[49][50][51] As a result, the syntheses of bifunctional NS 4 -BA and resulting bioconjugates are currently underway, with in vivo biodistribution and imaging studies planned in due course.…”

“…Gilpin et al studied the incorporation of 197m/g Hg via organometallic bonds using a cyclic bisarylmercury complex (Figure 1B), which showed good organ clearance and no retention in the kidney in a biodistribution study, indicating the complex may be stable in vivo, while Pietzsch et al reported a variety of 197m/g Hg labelled organic molecules (Figure 1C) obtained via electrophilic substitution to produce in vivo stable compounds. [25,26] Unlike the majority of previous work, which incorporates 197m/g Hg via organometallic bonds, this work aims to incorporate this theranostic pair into a radiopharmaceutical via the bifunctional chelator (BFC) approach. [2,5,19,20,23,25,26,28] BFCs link the radioisotope to a disease-specific targeting vector allowing selective and targeted delivery of the radiation payload to diseased cells.…”

“…[25,26] Unlike the majority of previous work, which incorporates 197m/g Hg via organometallic bonds, this work aims to incorporate this theranostic pair into a radiopharmaceutical via the bifunctional chelator (BFC) approach. [2,5,19,20,23,25,26,28] BFCs link the radioisotope to a disease-specific targeting vector allowing selective and targeted delivery of the radiation payload to diseased cells. [1,13,29,30] The BFC method in inorganic radiopharmaceutical design is attractive since all the synthesis of the chelate and biomolecule occurs before the addition of the radionuclide, enabling a 1-step labeling process, saving many half-lives of radioactivity.…”

The effect of disinfectants and antiseptics on co- and cross-selection of resistance to antibiotics in aquatic environments and wastewater treatment plants

“…Mercury (Hg) compounds are today mainly used in the form of organo derivates like nitromersol, thimerosal, merbromin and phenylmercuric nitrate. Organomercury are used less often in the west as disinfectants since they are considered toxic (Gilpin et al, 2021 ). Thimerosal is still used as an antiseptic in multi vaccine doses, especially in the third world countries (Geier et al, 2015 ).…”