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 [Ga-68-DOTA, Tyr(3)] octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its In-111-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 GaIII-complexed peptides. On hsst3 the situation was reversed, with a trend towards lower affinity of the GaIII peptides. A significantly increased internalisation rate was found in sst2-expressing cells for all Ga-67-labelled peptides. Internalisation into HEK-sst3 was usually faster for the In-111-labelled peptides. No internalisation was found into sst5. Biodistribution studies employing [Ga-67-DOTA, 1-Nal(3)] octreotide in comparison to [In-111-DOTA, 1-Nal(3)] octreotide and [Ga-67-DOTA, Tyr(3)] octreotide showed a significantly higher and receptor-mediated uptake of the two Ga-67-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 Ga-67/68-DOTA-octapeptides show distinctly better preclinical, pharmacological performances than the In-111-labelled peptides, especially on sst2-expressing cells and the corresponding animal models. They may be excellent candidates for further development for clinical studies.