Trithiols and their arsenic compounds for potential use in diagnostic and therapeutic radiopharmaceuticals

Abstract

Introduction Arsenic-72 (72As; 2.49 MeV β+, 26 h) and 77As (0.683 MeV β−, 38.8 h) have nuclear properties useful for positron emission tomography (PET) and radiotherapy applications, respectively. Their half-lives are sufficiently long for targeting tumors with antibodies, as well as peptides. Potential radiopharmaceuticals based on radioarsenic require development of suitable bifunctional chelates for stable conjugation of arsenic to vectors under in vivo conditions at high dilution. Methods The thiophilic nature of arsenic led to the synthesis and characterization of a simple trithiol ligand and its arsenic complex, and radiolabeling studies at the no carrier added (NCA) 77 As level. Results 1H- and 13C-NMR spectroscopy, electrospray ionization mass spectrometry (ESI-MS), and single crystal X-ray diffraction were used to characterize the trithiol ligand and its arsenic(III) complex. Radiotracer studies with no carrier added (NCA) 77As resulted in high radiolabeling yields (>96%) with high in vitro stability. Conclusions The high yield and stability of a single NCA 77As trithiol complex indicates this framework is suitable for developing matched pair agents for non-invasive in vivo PET imaging and radiotherapy of tumors with 72,77As. This is the first reported chelate developed for NCA radioarsenic and studies are underway for developing a trithiol bifunctional chelate conjugated to a targeting vector, such as a peptide or monoclonal antibody.

Intrinsic and Stable Conjugation of Thiolated Mesoporous Silica Nanoparticles with Radioarsenic

“…This clearly shows the negligible labeling yield of thiol-modified MSN with pentavalent radioarsenic. These results with nca radioarsenic are in good agreement with recent radioarsenic studies 45,46 and the well-established properties of bulk trivalent and pentavalent arsenic, as recently reviewed in the context of their protein binding properties, 47 which demonstrate high thiol binding for As(III) and negligible binding for As(V).…”

Chromatographic separation of germanium and arsenic for the production of high purity 77As

“…A trithiol ligand, namely 2-ethyl-2-(mercaptomethyl)propane-1,3-dithiol, was carried out as previously reported [17] in >98% yield of the 77 As-trithiol product ( Figure 8 ).…”

“…The synthesis of this [ 77 As]-labeled trithiol from methanol separated [ 77 As]arsenate has been reported [17]. Briefly, aqueous ammonium mercaptoacetate (25 mM), and 2-ethyl-2-(mercaptomethyl)propane-1,3-dithiol (trithiol ligand; 15 μM in absolute ethanol) were combined in a reaction vial.…”

“…Subsequently, enriched 76 Ge (98 ± 2) was recovered for reuse by elution with aqueous solution (neutral to basic). Greater than 98% radiolabeling yield of a 77 As-trithiol was observed from methanol separated [ 77 As]arsenate [17]. …”

Labelling with positron emitters of pnicogens and chalcogens

“…The thiophilic nature of arsenic led to the development of a small molecule, arsenic(III)trithiol(4‐ethyl‐2,6,7‐trithia‐1‐arsabicyclo[2.2.2]octane), which was translated to the nca 72/77 As a radiotracer level (cf Scheme ) . The nca bicyclic [ 77 As]arsenic trithiol was synthesized through the in situ reduction of arsenate to a reactive tris(monothiol)‐As(III) intermediate.…”