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.

Photochemical Reactions in the Synthesis of Protein–Drug Conjugates

“… Structures of various macrocyclic (left) and acyclic (right) chelates that were synthesised for photoradiosynthesis of 68 Ga‐, 89 Zr‐ and 111 In‐radiolabelled mAbs . Notably, this range of chelates is also suitable for complexation of other radioactive metal ions including, but not limited to, 64 Cu for positron emission tomography imaging, 67 Cu and 177 Lu for single‐photon‐emission computed tomography (SPECT) imaging and β‐therapy, and 225 Ac for α‐particle therapy …”

“…[41][42][43][44][45] Notably,t his range of chelates is also suitable for complexation of other radioactive metal ions including, but not limitedto, 64 Cu for positron emission tomographyimaging, 67 Cu and 177 Lu for single-photon-emission computed tomography (SPECT) imaging and b-therapy,and 225 Ac for a-particle therapy. [62,63] aqueous conditions, operates at am ild pH range (ca. [7][8][9], and is compatible with many formulation buffers used to stabilise clinical-grade preparationso fm anym Abs.…”

Room Temperature Al18F Labeling of 2‐Aminomethylpiperidine‐Based Chelators for PET Imaging

“…[2] For PET imaging, the selection of the best radionuclide for a given application is the most crucial decision because the physical half-life of the radionuclide must match the expected biological half-life of the radiotracer in vivo. [3] F-18 with t 1/2 = 109.8 min,~97 % β + -emission and a maximum positron energy of 635 keV can be easily produced in high quantities with an on-site cyclotron. Since the half-life of F-18 is long enough to allow multistep labeling reactions, but also short enough to avoid extended irradiation of patients, in the last decades several radiotracers based on F-18 have been developed.…”

Photochemische Konjugation und Eintopfradiomarkierung von Antikörpern für Immun‐PET

“…Klassische Verfahren zur Radiomarkierung von Proteinen umfassen in der Regel mehrere Schritte, bei denen das Protein zunächst gereinigt, an ein Chelat gekuppelt, isoliert, gelagert und danach radioaktiv markiert wird . Es gibt viele Kupplungsmethoden, in der Klinik jedoch beruhen die meisten radioaktiv markierten mAbs auf der Modifikation von Cystein (Thiolat) mit Reagentien auf Maleimidobasis oder der Funktionalisierung der Lysin‐NH 2 ‐Seitenkette mit N ‐Hydroxysuccinimid (NHS) oder Isothiocyanat (NCS) .…”