Trithiol ligand development for radioarsenic and radioantimony toward potential theranostic radiopharmaceutical agents

Abstract

Radiopharmaceuticals deliver radioactive drugs to specific target sites for imaging or therapy purposes, depending on the decay characteristics of the radionuclides. Potential radiopharmaceuticals are commonly designed via the bifunctional chelate approach, where the radionuclides are chelated with a ligand and linked to a targeting biomolecule. Combined therapeutic and diagnostic radionuclides ("theranostic pair") are of great interest to provide patients with the ability to diagnose, treat and evaluate treatment with follow-up imaging tools (e.g., 177Lu/68Ga). However, the truly matched pair radionuclides with identical chemistry yet different nuclear properties are rare (e.g., 64,67Cu, 44,47Sc, 135,131I). As one of the potential theranostic pairs, 72As (2.49 Mev [beta]+max, t1/2: 26 h) and 77As (0.683 Mev [beta]-max, t1/2: 38.8 h) enjoy suitable physical properties for radioimaging and therapy. Previous efforts on the development of 77As-labeled radiotracers, however, were found to form lipophilic compounds based on their log D7.4 values and biodistribution studies in normal mice. It is the aim of this work to address this issue through the synthesis of a new hydrophilic trithiol ligand and its 77As-labeled bioconjugates. Production of 77As and 72As is described. A new trithiol chelate with two carboxylic acid groups was developed and then conjugated to the RM2 peptide targeting gastrin releasing peptide receptors on prostate cancer with two different linkers, (Ser)2 and Glu-Ser. The radiolabeling of two radiotracers, [77As]As-trithiol-(Ser)2-RM2 and [77As]As-trithiol-Glu-Ser-RM2, and their in-vivo biodistributions in healthy male mice were performed and compared. Further, the work extends the trithiol complexation from arsenic to antimony given their chemical similarities. The chemistry between trithiol ligands and macroscopic-level antimony was investigated. Two antimony radionuclides were of particular interest, 117Sb as a positron emitter for imaging and 119Sb as an Auger emitter for radiotherapy. Radioantimony production and its radiolabeling with trithiol ligands were explored.