177Lu(III) - and 225Ac(III) -labelled bispidine conjugates targeting neuroendocrine tumours

Bispidines (3,7-diazabicyclo[3.3.1]nonane) and their derivatives act as bifunctional
chelators (BFC), combining the advantages of multidentate macrocyclic and acyclic
ligands (e.g., high kinetic inertness, rapid radiolabelling under mild conditions) [1]. This
bicyclic chelator system shows a great diversity in terms of its denticity and type of
functional groups, yielding a wide range of multidentate ligands that can bind a variety of
different metal ions [1-3]. In addition, they allow a facile functionalisation of targeting
molecules such as peptides, peptidomimetics, and bispecific antibodies which can also
be used as target modules for adapter CAR T-cell cross-linkage [1, 4]. Herein, we present
a nonadentate bispidine ligand labelled with [177Lu]Lu3+ and [225Ac]Ac3+ at mild
conditions. The radiometal complexes have been obtained with high radiochemical yields
(99%) and are stable in human serum [3]. This is unique so far, as many chelators are
not able to bind both LuIII and AcIII under mild conditions (physiological pH, T<40°C) with
fast complexation kinetics and high molar activities (>100 MBq/nmol for [177Lu]Lu3+ and
~0.2 MBq/nmol for [225Ac]Ac3+). For targeting, the chelator was functionalised with a
peptidic somatostatin analogue (Tyr3
-octreotate), which addresses the somatostatin
subtype receptor 2 in neuroendocrine tumours. Both 177Lu(III)- and 225Ac(III)-labelled
conjugates were investigated towards their binding affinity and internalization in a murine
pheochromocytoma (MPC) and human pancreatic carcinoid (BON1) tumour cell line and
were compared with [177Lu]Lu(III)- and [
225Ac]Ac(III)-DOTA-TATE. The presented
177Lu(III)- and 225Ac(III)-labelled bispidine-conjugates show favourable labelling kinetics
and high radiostabilities in human serum. The radioconjugates exhibited dissociation
constants in the lower nanomolar range (<10 nM) and high internalisation rates (>95 %)
in both cell lines. In comparison to the corresponding DOTA-radioconjugates, milder
radiolabelling conditions might facilitate the labelling of heat-sensitive biomolecules.
Thus, this bispidine chelator shows promising characteristics for future nuclear medicine
applications.

References:

[1] P. Comba et al., Dalton Trans. 2018, 47, 9202. [2] L. Abad‐Galán et al., Chem. Eur.
J. 2021, 27, 10303. [3] P. Cieslik et al., Bispidine derivatives and the use thereof.
EP20216739, 2020. [4] G. Singh et al., Chem. Eur. J. 2020, 26, 1989.