Genetic Code Expansion for Site-Specific Labeling of Antibodies with Radioisotopes.

Due to their target specificity, antibody-drug conjugates─monoclonal antibodies conjugated to a cytotoxic moiety─are efficient therapeutics that can kill malignant cells overexpressing a target gene. Linking an antibody with radioisotopes (radioimmunoconjugates) enables powerful diagnostics and/or closely related therapeutic applications, depending on the isotope. To generate site-specific radioimmunoconjugates, we utilized genetic code expansion and subsequent conjugation by inverse electron-demand Diels-Alder cycloaddition reactions.

Evaluation of different Zr-labeled synthons for direct labeling and tracking of white blood cells and stem cells in healthy athymic mice.

Cell based therapies are evolving as an effective new approach to treat various diseases. To understand the safety, efficacy, and mechanism of action of cell-based therapies, it is imperative to follow their biodistribution noninvasively. Positron-emission-tomography (PET)-based non-invasive imaging of cell trafficking offers such a potential.

Development and in vitro evaluation of new bifunctional Zr-chelators based on the 6-amino-1,4-diazepane scaffold for immuno-PET applications.

Introduction: Combination of hydroxamate bearing side chains with the 6-amino-1,4-diazepane scaffold provides a promising strategy for fast and stable Zr-labeling of antibodies. Following this approach, we hereby present the development, labeling kinetics and in vitro complex stability of three resulting bifunctional chelator derivatives both stand-alone and coupled to a model protein in comparison to different linear deferoxamine (DFO) derivatives.

Methods: The novel Zr-chelator HyADA was prepared via amide-coupling of separately synthesized 6-amino-1,4-diazepane-6-pentanoic acid and hydroxamate-containing side chains.

Squaric Acid-Based Radiopharmaceuticals for Tumor Imaging and Therapy.

Targeting vectors bound to a chelator represent a significant fraction of radiopharmaceuticals used nowadays for diagnostic and therapeutic purposes in nuclear medicine. The use of squaramides as coupling units for chelator and targeting vector helps to circumvent the disadvantages of several common coupling methods. This review gives an overview of the use of squaric acid diesters (SADE) as linking agents.

AAZTA-squaramide ester competing with DOTA-, DTPA- and CHX-A″-DTPA-analogues: Promising tool for Lu-labeling of monoclonal antibodies under mild conditions.

Background: Combining the advantages of both cyclic and acyclic chelator systems, AAZTA (1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) is well suited for complexation of various diagnostic and therapeutic radiometals such as gallium-68, scandium-44 and lutetium-177 under mild conditions. Due to its specificity for primary amines and pH dependent binding properties, squaric acid (SA) represents an excellent tool for selective coupling of the appropriate chelator to different target vectors. Therefore, the aim of this study was to evaluate radiolabeling properties of the novel bifunctional AAZTA-SA being coupled to a model antibody (bevacizumab) in comparison to DOTA-SA, DTPA-p-Bn-SA and CHX-A″-DTPA-p-Bn-SA using the therapeutic nuclide lutetium-177.

Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA chelators.

Background: Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelator-linker systems.

Using immuno-PET imaging to monitor kinetics of T cell-mediated inflammation and treatment efficiency in a humanized mouse model for GvHD.

Purpose: Hematopoietic stem cell transplantation is the only curative treatment for several hematological malignancies and immune deficiency syndromes. Nevertheless, the development of graft-versus-host disease (GvHD) after transplantation is a severe complication with high morbidity and mortality. The aim of this study was to image human T cells during GvHD development and their migration into GvHD-related organs.

Ga[Ga]-, In[In]-oxine: a novel strategy of radiolabeling of HPMA-based micelles.

Polymeric micelles are of increasing interest as drug delivery vehicles since they can accumulate in tumor tissue through EPR effect and deliver their hydrophobic cargo. The pharmacology can be visualized and quantified noninvasively by molecular imaging techniques. Here, a novel, fast and efficient technique for radiolabeling various HPMA-LMA based micellar aggregates with hydrophobic oxine-complexes of the trivalent radiometals Ga and In was investigated.