title: Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Radiological Chemistry, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Antunes
authors.forename: M
authors.initials: M
authors.lastname: Ginj
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: B
authors.initials: B
authors.lastname: Waser
authors.forename: R P
authors.initials: RP
authors.lastname: Baum
authors.forename: J C
authors.initials: JC
authors.lastname: Reubi
authors.forename: H
authors.initials: H
authors.lastname: Maecke
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005710:Gallium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D009928:Organ Specificity; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000737:chemistry; D051381:Rats; D011917:Rats, Inbred Lew; D012680:Sensitivity and Specificity; D013004:Somatostatin / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
chemical_list: D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D013004:Somatostatin