Publikationsrepositorium - Helmholtz-Zentrum Dresden-Rossendorf

Bispidines (3,7-diazabicyclo[3.3.1]nonane) and their derivatives act as bifunctional chelating agents (BFCAs). Combining the advantages of highly preorganised rigid macrocyclic ligands and the flexibility of open-chain ligands, bispidines are able to form highly stable complexes at mild reaction conditions with a broad range of di- and trivalent metal ions. Of particular interest, they allow the coupling to biological targeting vectors such as peptides, peptidomimetics, T cell receptor derivatives as well as any kind of natural and recombinant antibody derivatives to construct effective radiopharmaceuticals for diagnostic and therapeutic purposes. Here, we present a nonadentate bispidine ligand (Figure 1), which forms stable and inert complexes with [177Lu]LuCl3, [225Ac]AcCl3 and [111In]InCl3 at mild conditions. This is unique so far, as few chelators are able to tightly bind both Lu(III) and Ac(III) under mild conditions
(physiological pH, T<40°C) with fast complexation kinetics. We investigated the thermodynamic and kinetic properties of the radio-complexes. For targeting, the chelator was functionalised with a peptidic somatostatin analogue (Tyr3-octreotate, TATE), which addresses the somatostatin subtype receptor 2 in neuroendocrine tumors. The bispidine-TATE conjugate was labelled with 177Lu(III) and 225Ac(III) and investigated in SSTR2-positive mouse pheochromocytoma (MPC) and human pancreatic carcinoid tumour (BON-SSTR2) cell lines. Moreover, quantitative small animal SPECT imaging showed specific uptake of the [177Lu]Lu-conjugate in vivo in naturally SSTR2-positve MPC tumour allografts. Some structural optimisation will be required to further reduce off-target accumulation. However, the bispidine chelator shows a promising potential for a broad application in nuclear medicine, both in imaging and radionuclide therapy.