Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?
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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.
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.
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 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.
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.
KeywordsSomatostatin receptors Gallium-68 Indium-111 Radiopeptides Imaging
P. Antunes acknowledges the PhD Fellowship of the Fundação para a Ciência e Tecnologia (Ref. SFRH/BD/3136/2000). In addition, P. Antunes, M. Ginj, M. Walter and H. Maecke acknowledge the support from the Swiss National Science Foundation project No. 3100A0-100390, BBW project No C00.0091, and the network of excellence, European Molecular Imaging Laboratories (EMIL). The support provided by Novartis Pharma in respect of ESI-MS analysis is gratefully acknowledged. We thank Dr. S. Schulz for the sst3-transfected human embryonic kidney 293 cells. The authors thank K. Hinni and S. Tschumi for biological technical assistance. This work was performed within the COST B12 Action.
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