A New Synthesis of TE2A—a Potential Bifunctional Chelator for 64Cu

Abstract

Purpose The development of a new bifunctional chelator, which holds radiometals strongly in living systems, is a prerequisite for the successful application of diseasespecific biomolecules to medical diagnosis and therapy. Recently, TE2A was reported to make kinetically more stable Cu(II) complexes than TETA. Herein, we report a new synthetic route to TE2A and explore its potential as a bifunctional chelator. Methods TE2A was synthesized using the regioselective alkylation of benzyl bromoacetate and successive deprotection of the methylene bridge and benzyl group. Salt-free TE2A was radiolabeled with 64 Cu and microPET imaging was performed to follow the clearance pattern of the 64 Cu-TE2A complex. TE2A was conjugated with cyclic RGD peptide and the TE2A-c(RGDyK) conjugate was radiolabeled with 64 Cu. Results TE2A was prepared in salt-free form from cyclam in an overall yield of 74%. The microPET images showed that 64 Cu-TE2A is excreted rapidly from the body by the kidney and liver. TE2A was successfully conjugated with c(RGDyK) peptide through one carboxylate group and the TE2A-c(RGDyK) conjugate was radiolabeled with 64 Cu in 94% yield within 30 min. Conclusion TE2A can be used by itself as a bifunctional chelator without any further structural modification.

Chelators for copper radionuclides in positron emission tomography radiopharmaceuticals

“… 32 In a follow-up paper, a new synthesis of the salt-free TE2A was reported that was conjugated to c(RGDyK), but no biodistribution data were reported. 33 Zhang et al . reported a multivalency platform based on the DOTA chelator using c(RGDyK) with no space between the c and (RGDyK) as a model peptide.…”

“…reported a synthesis of TE2A ( 12 ), and the acid decomplexation and reduction potential measurements indicated that Cu‐TE2A is more stable than Cu‐TETA, on the basis of rat biodistribution data showing significantly lower retention of 64 Cu‐TE2A than 64 Cu‐TETA in kidney and liver at 24 h post injection, suggesting a lower extent of demetallation in vivo . In a follow‐up paper, a new synthesis of the salt‐free TE2A was reported that was conjugated to c(RGDyK), but no biodistribution data were reported . Zhang et al .…”

In Vivo Albumin‐Binding of a C‐Functionalized Cyclam Platform for 64Cu‐PET/CT Imaging in Breast Cancer Model

“…The approach to GluCAB‐1 Mal for copper complexation was to use a TE2A, a cyclam platform, functionalized with two acetate arms [28–30] . The cyclam was selected as the most appropriate based‐backbone, with a cavity better suited for copper cation able to form highly stable and inert complexes [31,32] .…”

In Vivo Albumin-Binding of a C-Functionalized Cyclam Platform for 64Cu-PET/CT Imaging in Breast Cancer Model

“…24,25 For copper complexation, the cyclam backbone was selected as the most appropriate since the cavity is better suited for this cation with highly stable and inert complexes being formed; 28,29 it also appeared to be the most tunable platform considering all the recent successful studies in 64 Cu-PET imaging using cyclam-based chelators. 30,31,32,33,34,35 The approach to Glu-CAB-1 Mal was to use the cyclam platform functionalized with two acetate arms, namely TE2A. Although other cyclam derivatives have proved to be more suitable for the application, TE2A presented the advantage of being a decent copper(II) chelator, 36 while offering two remaining secondary amines that could be functionalized ( Figure 2) for passive and active targeting.…”

“…37 Furthermore, the synthesis of TE2A is rather simple and well-described in literature. 34 However, access to GluCAB-1 Mal was not simple, the secondary amine functions of the TE2A precursor (its tert-butyl diester derivative) being equivalent. A delicate statistical functionalization of these latter amines with the targeting groups was required leading to difficult purifications and poor yields.…”