Synthesis of one-, two- and three-ring macrocyclic, bifunctional compounds for use in radiolabelling monoclonal antibodies

Abstract

The synthesis of new linked bis-and tris-ring tetraazamacrocyclic (bifunctional) reagents for use in an alternative strategy for radiolabelling antibodies is described. For comparison with the above systems, a new single ring bifunctional system incorporating a dioxocyclam ring is also reported.

Extending the Scope of the C-Functionalization of Cyclam via Copper(I)-Catalyzed Alkyne–Azide Cycloaddition to Bifunctional Chelators of Interest

“…Thanks to its secondary amines, cyclam can be selectively or fully N -functionalized to complete the coordination sphere of a metal, leading to other thermodynamic and kinetic properties . The N -introduction of pendant functions or groups leads to so-called bifunctional chelating agents that provide a wide range of applications (Chart ) such as modification of thermal properties (compound A ), catalytic reduction of CO 2 (compound B ), but also for medical purposes, including cyclams bearing a bioconjugation function (compound C ) or a targeting group such as a biotin (compound D ) . More sophisticated structures with different functions on the nitrogen atoms have also been described, such as compound E , a nebramine-cyclam conjugate that enhances the efficacy of β-lactam antibiotics, or F which was developed for targeted positron emission tomography (PET) tumor imaging after radiolabeling with copper-64 …”

Extending the scope of the C-functionalization of cyclam via Copper(I)-catalyzed Alkyne-Azide Cycloaddition to bifunctional chelators of interest

“…4 Thanks to its secondary amines, cyclam can be selectively or fully N-functionalized to complete the coordination sphere of a metal, leading to other thermodynamic and kinetic properties. 5 The N-introduction of pendant functions or groups leads to so-called bifunctional chelating agents that provide a wide range of applications (Chart 1) such as modification of thermal properties (compound A), 6 catalytic reduction of CO2 (compound B), 2 but also for medical purposes, including cyclams bearing a bioconjugation function (compound C) 7 or a targeting group such as a biotin (compound D). 8 These are only selected examples of a larger list.…”

Investigation of Novel Bis- and Tris-tetraazamacrocycles for Use in the Copper-64 (64Cu) Radiolabeling of Antibodies with Potential To Increase the Therapeutic Index for Drug Targeting

“…A series of new mono-, bis-, and tris-ring macrocyclic bifunctional compounds of types L1-L5 for use in radiolabeling monoclonal antibodies have been synthesized. (see Figure 2) (22). These new bis-and tris-cyclic ligands have the potential to yield radioimmunoconjugates with enhanced specific activities compared to corresponding single-ring systems, since two or three metal ions may potentially be attached via each linkage site on the mAb between the bifunctional compound and the mAb.…”