Metal-ion-dependent biological properties of a chelator-derived somatostatin analogue for tumour targeting

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 (sstl-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 [CoII(dota)]2- and [Ga III(dota)]- whose X-ray structures have been determined. Both chelates show six-fold coordination in pseudooctahedral arrangements. © 2008 Wiley-VCH Verlag GmbH & Co. KGaA.