Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

Purpose: Gallium-68 is a metallic positron emitter with a half-life of 68 min that is ideal for the in vivo use of small molecules, such as [ ⁶⁸Ga-DOTA,Tyr³]octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its ¹¹¹In-labelled congener. The purpose of this study was to evaluate whether third-generation somatostatin-based, radiogallium-labelled peptides show the same superiority. Methods: Peptides were synthesised on solid phase. The receptor affinity was determined by in vitro receptor autoradiography. The internalisation rate was studied in AR4-2J and hsst-HEK-transfected cell lines. The pharmacokinetics was studied in a rat xenograft tumour model, AR4-2J. Results: All peptides showed high affinities on hsst2, with the highest affinity for the Ga^III-complexed peptides. On hsst3 the situation was reversed, with a trend towards lower affinity of the Ga^III peptides. A significantly increased internalisation rate was found in sst2-expressing cells for all ⁶⁷Ga-labelled peptides. Internalisation into HEK-sst3 was usually faster for the ¹¹¹In- labelled peptides. No internalisation was found into sst5. Biodistribution studies employing [⁶⁷Ga-DOTA,1-Nal³]octreotide in comparison to [¹¹¹In-DOTA,1-Nal³]octreotide and [ ⁶⁷Ga-DOTA,Tyr³]octreotide showed a significantly higher and receptor-mediated uptake of the two ⁶⁷Ga-labelled peptides in the tumour and somatostatin receptor-positive tissues. A patient study illustrated the potential advantage of a broad receptor subtype profile radiopeptide over a high-affinity sst2-selective radiopeptide. Conclusion: This study demonstrates that ^67/68Ga-DOTA-octapeptides show distinctly better preclinical, pharmacological performances than the ¹¹¹In-labelled peptides, especially on sst2-expressing cells and the corresponding animal models. They may be excellent candidates for further development for clinical studies.