Advances in macrocyclic chelators for positron emission tomography imaging

Abstract

In recent years, radiometals have been successfully applied to medicine because of their breadth of decay properties and increased production and availability. Bifunctional chelators play a key role in radiometal‐based radiopharmaceuticals, affecting the labeling, targeting, and pharmacokinetics of bioconjugations and ensuring the stable complexation of the metal in vivo. The capacity of macrocycles to form complexes with extremely high thermodynamics, kinetics, and stability compared to acyclic chelators continues to pique the curiosity of pharmacists and biochemists among all prospective chelators utilized for the radiometal chelation. As new imaging modalities and therapeutic targets develop, the discovery of novel ligand structures with suitable chemical and biological features encourages the modification of chelators with charge and chemical properties. Herein, we present a comprehensive review of developments of macrocyclic chelators for PET radiopharmaceuticals, including innovative chelating agents with new structures and known chelating agent modifications, and their physical‐chemical properties, as well as their biological characteristics and applications in vivo.

Integrating Prior Chemical Knowledge into the Graph Transformer Network to Predict the Stability Constants of Chelating Agents and Metal Ions

“…This underscores the crucial importance of the complex's stability. 6 An ideal chelator should possess good thermodynamic stability, kinetic inertness, and favorable in vivo properties. Thermodynamic stability is a significant indicator for assessing the metal affinity of a chelator, which is evaluated by the stability constants (log K) reflecting the complex equilibrium between chelators and metal ions.…”

“…The primary role of chelators is to form stable coordination complexes with radiometals, preventing the release of free metal ions into the body. This underscores the crucial importance of the complex’s stability . An ideal chelator should possess good thermodynamic stability, kinetic inertness, and favorable in vivo properties.…”

Coordination Chemistry of Sulfur-Containing Bifunctional Chelators: Toward in Vivo Stabilization of 64Cu PET Imaging Agents for Alzheimer’s Disease

“…A variety of copper chelators have been designed and developed to prevent unproductive radionuclide release. To avoid transmetalation, many azamacrocyle ligand frameworks, such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); and structurally constrained cross-bridged cyclen, cyclam, and sarcophagine derivatives have been designed to form Cu­(II) complexes with excellent thermodynamic stability and kinetic inertness. ,− In order to minimize the reduction induced demetalation pathway, it is believed that chelators that can stabilize both Cu­(II) and Cu­(I) are advantageous. However, due to the dramatic differences in coordination preferences between Cu­(II) and Cu­(I), only a few examples have been reported in regard to developing ligand frameworks that can stabilize the Cu center at both oxidation states.…”

Molecular imaging for better theranostics

“…In response to the current shortage of specific imaging tracers, several novel nuclear imaging probes, in the forms of small molecules, peptides, oligonucleotides [13], antibodies [14][15][16], and antibody fragments, have been developed and evaluated in not only animals but also first-in-human studies. New tracers demand updated theories on "structure-effect" relationships [17], and studies regarding the choice of radionuclides, chelators, linkers, functional groups, molecular modifications, and overall drug pharmacokinetics have been another research hot spot [18]. Other than drug development to see disease lesions clearer, accurate image quantification and reconstruction have been vital in helping researchers and clinicians understand disease progress and underlying mechanisms.…”