Chemical aspects of metal ion chelation in the synthesis and application antibody-based radiotracers

Abstract

Radiometals are becoming increasingly accessible and are utilized frequently in the design of radiotracers for imaging and therapy. Nuclear properties ranging from the emission of γ-rays and β⁺ -particles (imaging) to Auger electron and β^- and α-particles (therapy) in combination with long half-lives are ideally matched with the relatively long biological half-life of monoclonal antibodies in vivo. Radiometal labeling of antibodies requires the incorporation of a metal chelate onto the monoclonal antibody. This chelate must coordinate the metal under mild conditions required for the handling of antibodies, as well as provide high kinetic, thermodynamic, and metabolic stability once the metal ion is coordinated to prevent release of the radionuclide before the target site is reached in vivo. Herein, we review the role of different radiometals that have found applications of the design of radiolabeled antibodies for imaging and radioimmunotherapy. Each radionuclide is described regarding its nuclear synthesis, coordinative preference, and radiolabeling properties with commonly used and novel chelates, as well as examples of their preclinical and clinical applications. An overview of recent trends in antibody-based radiopharmaceuticals is provided to spur continued development of the chemistry and application of radiometals for imaging and therapy.

Keywords: chelates; coordination chemistry; immuno-PET; radioimmunotherapy; radiometals.

Figure 1

Stacked bar chart showing the total number of US-FDA approved New Molecular Entities from 2011 until August 2017 with a breakdown showing the contribution from mAb-based agents and other drugs. * Data available until 08/2017.

Figure 2

Schematic representation of a radiolabelled mAb involving chemical modification of the protein using covalent bond formation to a radiometal binding chelate via a linker group.

Figure 3

Chemical structures of selected chelates that have been employed for complexation of various radiometal ions including those of copper, gallium, indium, yttrium, lutetium, actinium and beyond.

Figure 4

Chemical conjugation of TETA and BAT-2IT to antibodies coupling to the ε-NH₂ group of lysine residues.

Figure 5

Chemical structures of selected bifunctional chelates that have been developed for derivatisation of proteins and complexation of ⁸⁹Zr⁴⁺ ions.

Figure 6

Chemical structures of ^99mTc chelates that incorporate different ‘^99mTc-cores’.

Figure 7

Chemical structures of various reagents used for oxidative radiolabelling of proteins with iodine radionuclides.

Figure 8

Chemical structures of selected chelates that have been employed for complexation of yttrium, lutetium, bismuth, lead and actinium.