Theranostic and matched pair radionuclides as radiopharmaceutical as for imaging and radiotherapy
Authors:   , Najafi Khosroshahi Firouzeh 
Published: December 2023

The main focus of this dissertation is on the development of arsenic and rhenium radiopharmaceuticals as potential theranostic candidates. Chapter 2 focuses on 72,77. As radiopharmaceuticals for potential PET imaging and therapy: Synthesis, evaluation and biological studies of a linkable trithiol ligand with an improved hydrophilicity. Arsenic-72 and 77As are a suitable radioisotope matched pair for development of theranostic radiopharmaceuticals. Bombesin (BBN) peptide analogues generally target gastrin-releasing peptide (GRP) receptors expressed in the pancreas of normal mice and human cancers of the prostate. Previous biodistribution studies with 77As-trithiol(a)-BBN(7-14)NH2 in normal mice showed high lipophilicity of 77As-trithiol(a)-BBN(7-14)NH2 followed by fast and high hepatobiliary excretion and no significant pancreatic uptake. A new trithiol bifunctional chelate with an improved hydrophilicity and flexibility in the structure for conjugation to targeting biomolecules was developed. This new trithiol chelate was conjugated to the RM2 peptide (a GRP receptor antagonist) through a two serine (Ser) spacer. The trithiol(b)-(Ser)2-RM2 conjugate was radiolabeled with no carrier added 77As and conditions were optimized to maximize radiolabeling yield. Biodistribution studies in normal mice were conducted and is herein reported. Chapter 3 examines the development and synthesis of trithiol conjugated Herceptin and radiolabeling of the conjugate with arsenic radioisotopes. Radiolabeling monoclonal antibodies (mAbs) with a vast range of radionuclides are being utilized in clinical diagnosis and therapy. The idea of labeling monoclonal antibodies with radioactive arsenic isotopes for the purpose of molecular imaging have been examined in the past. Bifunctional chelating agents (BCAs) have been developed to facilitate covalent bonding between a radiometal chelate to mAbs for the purpose of higher in vivo stability of the radiometal chelate followed by reducing the amount of free radiometal uptake in normal and non-targeted tissue. 1 Herceptin, known as Trastuzumab, is an IgG1 kappa-containing human framework region with the complementarity-determining regions of a murine anti-p185 Her2 antibody. Herceptin has anti-angiogenesis effect on Her2 positive breast cancer tumors. A method for conjugation of a new trithiol ligand with an improved hydrophilicity to Herceptin followed by radiolabeling with arsenic radioisotopes for diagnosis and treatment of Her2-positive breast cancer tumors was investigated. The method involved preparing amine-reactive esters of a carboxylate group on a trithiol ligand with Nhydroxysuccinimide (NHS) and 1-ethyl-3-(3-imethylaminopropyl)carbodiimide (EDC) resulting in a stable trithiol-NHS active ester. 2, 3 A previously reported simple method for conjugation of monoclonal antibodies with NHS-trithiol active esters in aqueous solution was utilized for the conjugated trithiol-Herceptin compound. Radiolabeling attempts of the conjugated Herceptin with [77As]AsSR are underway. 4-6 Chapter 4 investigates the synthesis and evaluation of a monoamine monoamide dithiol (MAMA) ligand with an improved hydrophilicity for developing bifunctional chelators and their 186/188Re compounds. A series of NxS4-x tetradentate chelates are used to bind to oxo-rhenium core. Small peptides such as Bombesin are favorable biomolecules for delivering a radiophamaceutical to specifc target sites in the body. Various MAMA analogues including 222-MAMA, 222-MAMA (N-6-Ahx-OEt), and 222-MAMA (N-6-Ahx-BBN (7-14)NH2 have been previously synthesized and radiolabeled with 186Re (high and low specific activity). 7 Biological evaluation of 186ReO 222-MAMA (N-6-Ahx BBN (7-14)NH2) was previously studies in mouse models bearing PC-3 human prostate cancer cells, which showed high in vivo stability and demonstrated high binding affinity to the GRP receptors on PC3 cells. However, 186ReO(222-MAMA (N-6-Ahx-OEt)) showed lipophilicity and was excreted more through the hepatobiliary and GI system relative to the renal system. 7 The ongoing research presented in chapter 4 focuses on synthesis and evaluation of a 222-MAMA chelate with an improved hydrophilicity followed by radiolabeling with 99mTc and 186Re. Conjugation of 222-MAMA-(N-6-Ahx-OEt) to RM2 peptide as the targeting vector is ongoing.