HNODThia: A Promising Chelator for the Development of Cu Radiopharmaceuticals.

Herein, we present the synthesis and coordination chemistry of copper(II) and zinc(II) complexes of two novel heterocyclic triazacyclononane (tacn)-based chelators (H and ). The chelator H was further derivatized to obtain a novel PSMA-based bioconjugate () and a bifunctional photoactivatable azamacrocyclic analogue, , for the development of copper-64 radiopharmaceuticals. Cu radiolabeling experiments were performed on the different metal-binding chelates, whereby quantitative radiochemical conversion (RCC) was obtained in less than 10 min at room temperature.

Charting the Chemical and Mechanistic Scope of Light-Triggered Protein Ligation.

The creation of discrete, covalent bonds between a protein and a functional molecule like a drug, fluorophore, or radiolabeled complex is essential for making state-of-the-art tools that find applications in basic science and clinical medicine. Photochemistry offers a unique set of reactive groups that hold potential for the synthesis of protein conjugates. Previous studies have demonstrated that photoactivatable desferrioxamine B (DFO) derivatives featuring a para-substituted aryl azide (ArN) can be used to produce viable zirconium-89-radiolabeled monoclonal antibodies (Zr-mAbs) for applications in noninvasive diagnostic positron emission tomography (PET) imaging of cancers.

Photoactivatable bis(thiosemicarbazone) derivatives for copper-64 radiotracer synthesis.

In recent years, copper-64 and copper-67 have been considered as a useful theranostic pair in nuclear medicine, due to their favourable and complementary decay properties. As Cu and Cu are chemically identical, development of both existing and new bifunctional chelators for Cu imaging agents can be readily adapted for the Cu-radionuclide. In this study, we explored the use of photoactivatable copper chelators based on the asymmetric bis(thiosemicarbazone) scaffold, HATSM/en, for the photoradiolabelling of protein.

The Influence of a Polyethylene Glycol Linker on the Metabolism and Pharmacokinetics of a Zr-Radiolabeled Antibody.

Most experimental work in the space of bioconjugation chemistry focuses on using new methods to construct covalent bonds between a cargo molecule and a protein of interest such as a monoclonal antibody (mAb). Bond formation is important for generating new diagnostic tools, yet when these compounds advance to preclinical and studies, and later for translation to the clinic, understanding the fate of potential metabolites that arise from chemical or enzymatic degradation of the construct is important to obtain a full picture of the pharmacokinetic performance of a new compound. In the context of designing new bioconjugate methods for labeling antibodies with the positron-emitting radionuclide Zr, we previously developed a photochemical process for making Zr-mAbs.

Microfluidic Preparation of Zr-Radiolabelled Proteins by Flow Photochemistry.

Zr-radiolabelled proteins functionalised with desferrioxamine B are a cornerstone of diagnostic positron emission tomography. In the clinical setting, Zr-labelled proteins are produced manually. Here, we explore the potential of using a microfluidic photochemical flow reactor to prepare Zr-radiolabelled proteins.

Expanding the Chemistry Palette for Radiotracer Synthesis.

The synthesis, characterisation and application of radiolabelled compounds for use in diagnostic and therapeutic medicine requires a diverse skill set. This article highlights a selection of our ongoing projects that aim to provide new synthetic methods and radiochemical tools for building molecular imaging agents with various radionuclides.

Light-induced synthesis of protein conjugates and its application in photoradiosynthesis of Zr-radiolabeled monoclonal antibodies.

Efficient methods to functionalize proteins are essential for the development of many diagnostic and therapeutic compounds, such as fluorescent probes for immunohistochemistry, zirconium-89 radiolabeled mAbs (Zr-mAbs) for positron emission tomography and antibody-drug conjugates (ADCs). This protocol describes a step-by-step procedure for the light-induced functionalization of proteins with compounds bearing the photochemically active aryl azide group. As an illustration of the potential utility of our approach, this protocol focuses on the synthesis of Zr-mAbs using photoactivatable derivatives of the metal ion binding chelate desferrioxamine B (DFO).

Light-Activated Protein Conjugation and Zr-Radiolabelling with Water-Soluble Desferrioxamine Derivatives.

Protein-conjugates are vital tools in biomedical research, drug discovery and imaging science. For example, functionalised monoclonal antibodies (mAbs) coupled to the desferrioxamine B (DFO) chelate and radiolabelled with Zr ions are used as radiopharmaceuticals for diagnostic positron emission tomography (PET). In this context, protein functionalisation requires the formation of a covalent bond that must be achieved without compromising the biological properties of the mAb.

Efficient Blocking of Enterovirus 71 Infection by Heparan Sulfate Analogues Acting as Decoy Receptors.

Enterovirus 71 (EV71) is a major etiological agent of hand, foot, and mouth disease, for which there is no antiviral therapy. We have developed densely sulfated disaccharide heparan sulfate (HS) analogues that are potent small molecule inhibitors of EV71 infection, binding to the viral capsid and acting as decoy receptors to block early events of virus replication. The simplified structures, more potent than defined HS disaccharides and with no significant anticoagulant activity, offer promise as anti-EV71 agents.