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.
- 2.Maina T, Nock B, Nikolopoulou A, Sotiriou P, Loudos G, Maintas D, et al. [99mTc]Demotate, a new 99mTc-based [Tyr3]octreotate analogue for the detection of somatostatin receptor-positive tumours: synthesis and preclinical results. Eur J Nucl Med Mol Imaging 2002;29:742–53.PubMedCrossRefGoogle Scholar
- 3.Decristoforo C, Mather SJ, Cholewinski W, Donnemiller E, Riccabona G, Moncayo R. 99mTc-EDDA/HYNIC-TOC: a new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours; first clinical results and intra-patient comparison with 111In-labelled octreotide derivatives. Eur J Nucl Med 2000;27:1318–25.PubMedCrossRefGoogle Scholar
- 4.Storch D, Behe M, Walter MA, Chen J, Powell P, Mikolajczak R, et al. Evaluation of [99mTc/EDDA/HYNIC0]octreotide derivatives compared with [111In-DOTA0,Tyr3, Thr8]octreotide and [111In-DTPA0]octreotide: does tumor or pancreas uptake correlate with the rate of internalization? J Nucl Med 2005;46:1561–9.PubMedGoogle Scholar
- 5.de Jong M, Bakker WH, Krenning EP, Breeman WA, van der Pluijm ME, Bernard BF, et al. Yttrium-90 and indium-111 labelling, receptor binding and biodistribution of [DOTA0,d-Phe1,Tyr3]octreotide, a promising somatostatin analogue for radionuclide therapy. Eur J Nucl Med 1997;24:368–71.PubMedCrossRefGoogle Scholar
- 7.Smith-Jones PM, Stolz B, Bruns C, Albert R, Reist HW, Fridrich R, et al. Gallium-67/gallium-68-[DFO]-octreotide—a potential radiopharmaceutical for PET imaging of somatostatin receptor-positive tumors: synthesis and radiolabeling in vitro and preliminary in vivo studies. J Nucl Med 1994;35:317–25.PubMedGoogle Scholar
- 19.Eisenwiener KP, Prata MI, Buschmann I, Zhang HW, Santos AC, Wenger S, et al. NODAGATOC, a new chelator-coupled somatostatin analogue labeled with [67/68Ga] and [111In] for SPECT, PET, and targeted therapeutic applications of somatostatin receptor (hsst2) expressing tumors. Bioconjug Chem 2002;13:530–41.PubMedCrossRefGoogle Scholar
- 20.Heppeler A, Froidevaux S, Mäcke HR, Jermann E, Béhé M, Powell P, et al. Radiometal-labelled macrocyclic chelator-derivatised somatostatin analogue with superb tumour-targeting properties and potential for receptor-mediated internal radiotherapy. Chemistry A European Journal 1999;5:1016–23.Google Scholar
- 23.Kowalski J, Henze M, Schuhmacher J, Maecke HR, Hofmann M, Haberkorn U. Evaluation of positron emission tomography imaging using [68Ga]-DOTA-D Phe1-Tyr3-octreotide in comparison to [111In]-DTPAOC SPECT. First results in patients with neuroendocrine tumors. Mol Imaging Biol 2003;5:42–8.PubMedCrossRefGoogle Scholar
- 27.Dimitrakopoulou-Strauss A, Georgoulias V, Eisenhut M, Herth F, Koukouraki S, Macke HR, et al. Quantitative assessment of SSTR2 expression in patients with non-small cell lung cancer using 68Ga-DOTATOC PET and comparison with 18F-FDG PET. Eur J Nucl Med Mol Imaging 2006;33:823–30.PubMedCrossRefGoogle Scholar
- 28.Baum R, Niesen A, Leonhardi J, Wortmann R, Mueller D, Roesch F. Receptor PET/CT imaging of neuroendocrine tumours using the Ga-68 labelled, high affinity somatostatin analogue DOTA-1-Nal3 octreotide (DOTA-NOC): clinical results in 327 patients. Eur J Nucl Med Mol Imaging 2005;32 Suppl 1:S54–5.Google Scholar
- 29.Roesch F, Zhernosekov K, Filosofov D, Jahn M, Jennewein M, Baum R, et al. Processing of Ge-68/Ga-68 generator eluates for labeling of biomolecules via bifunctional chelators. J Nucl Med 2006;47 Suppl 1:162P.Google Scholar
- 30.Baum R, Schmücking M, Wortmann R, Müller M, Zhernosekov K, Rösch F. Receptor PET/CT using the Ga-68 labelled somatostatin analog DOTA-1-Nal3-octreotide (DOTA-NOC): clinical experience in 140 patients. Nuklearmedizin 2005;44:A57.Google Scholar
- 40.Decristoforo C, von Guggenberg E, Haubner R, Rupprich M, Schwarz S, Virgolini I. Radiolabeling of DOTA-derivatised peptides with 68Ga via a direct approach—optimization and routine clinical application. Nuklearmedizin 2005;44:A191–2.Google Scholar
- 41.Hofmann M, Oei M, Boerner AR, Maecke H, Geworski L, Knapp WH, et al. Comparison of Ga-68-DOTATOC and Ga-68-DOTANOC for radiopeptide PET. Nuklearmedizin 2005;44:A58.Google Scholar