Metal-Ion-Dependent Biological Properties of a Chelator-Derived Somatostatin Analogue for Tumour Targeting

Graphical Abstract

Targeted! Improved pharmacokinetics and tumour targeting of a 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid conjugated somatostatin analogue has been achieved by its coupling to the positron emitter ⁵⁵Co (⁵⁷Co; see figure). The structural features of the (radio)metal complex determine its in vivo properties.

Abstract

Somatostatin-based radioligands have been shown to have sensitive imaging properties for neuroendocrine tumours and their metastases. The potential of [⁵⁵Co(dotatoc)] (dotatoc =4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-ylacetyl-D-Phe-(Cys-Tyr-D-Trp-Lys-Thr-Cys)-threoninol (disulfide bond)) as a new radiopharmaceutical agent for PET has been evaluated. ⁵⁷Co was used as a surrogate of the positron emitter ⁵⁵Co and the pharmacokinetics of [⁵⁷Co(dotatoc)] were investigated by using two nude mouse models. The somatostatin receptor subtype (sst1–sst5) affinity profile of [^natCo(dotatoc)] on membranes transfected with human somatostatin receptor subtypes was assessed by using autoradiographic methods. These studies revealed that [⁵⁷Co(dotatoc)] is an sst2-specific radiopeptide which presents the highest affinity ever found for the sst2 receptor subtype. The rate of internalisation into the AR4-2J cell line also was the highest found for any somatostatin-based radiopeptide. Biodistribution studies, performed in nude mice bearing an AR4-2J tumour or a transfected HEK-sst2 cell-based tumour, showed high and specific uptake in the tumour and in other sst-receptor-expressing tissues, which reflects the high receptor binding affinity and the high rate of internalisation. The pharmacologic differences between [⁵⁷Co(dotatoc)] and [⁶⁷Ga(dotatoc)] are discussed in terms of the structural parameters found for the chelate models [Co^II(dota)]²⁻ and [Ga^III(dota)]⁻ whose X-ray structures have been determined. Both chelates show six-fold coordination in pseudo-octahedral arrangements.