Trithiol compounds—tricky but valuable: the design and synthesis of ligands for stabilizing radioarsenic for radiopharmaceutical development
This chapter describes the development of novel trithiols for use as bifunctional chelators for no-carrier-added arsenic radioisotopes. A model trithiol (2-ethyl-2-(mercaptomethyl)propane) was synthesized with thiocyanate protecting groups, and the radioarsenic chemistry was developed. Conversion of the model trithiol into a bifunctional trithiol chelator that was amenable to peptide or antibody conjugation proved to be challenging. The first analogue involved using Cu(II)-mediated click chemistry to add a carboxylic acid moiety for peptide conjugation resulted in a very lipophilic radioarsenic bioconjugate. Synthesis of a hydrophilic trithiol conjugate involved redesign of the synthetic scheme, including changing the starting material (isophthalic acid rather than 1,1,1-tris(hydroxymethyl)propane), the thiol protecting groups (trityl rather than thiocyanate), and the leaving groups (bromide rather than tosyl) utilized.
