title: Comparative biodistribution of 12 ¹¹¹In-labelled gastrin/CCK2 receptor-targeting peptides.
abstract: OBJECTIVE
  Cholecystokinin 2 (CCK-2) receptor overexpression has been demonstrated in various tumours such as medullary thyroid carcinomas and small-cell lung cancers. Due to this high expression, CCK-2 receptors might be suitable targets for radionuclide imaging and/or radionuclide therapy. Several CCK-2 receptor-binding radiopeptides have been developed and some have been tested in patients. Here we aimed to compare the in vivo tumour targeting properties of 12 (111)In-labelled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated gastrin/CCK2 receptor-binding peptides.
  
  
  METHODS
  Two CCK8-based peptides and ten gastrin-based peptide analogues were tested. All peptides were conjugated with DOTA and labelled with (111)In. Biodistribution studies were performed in mice with subcutaneous CCK2/gastrin receptor-expressing tumours and with receptor-negative tumours contralaterally. Biodistribution was studied by counting dissected tissues at 1 and 4 h after injection.
  
  
  RESULTS
  Both the CCK analogues displayed relatively low tumour uptake (approximately 2.5%ID/g) as compared to minigastrin analogues. Two linear minigastrin peptides (MG0 and sargastrin) displayed moderate tumour uptake at both 1 and 4 h after injection, but also very high kidney uptake (both higher than 48%ID/g). The linear MG11, lacking the penta-Glu sequence, showed lower tumour uptake and also low kidney uptake. Varying the N-terminal Glu residues in the minigastrin analogues led to improved tumour targeting properties, with PP-F11 displaying the optimal biodistribution. Besides the monomeric linear peptides, a cyclized peptide and a divalent peptide were tested.
  
  
  CONCLUSIONS
  Based on these studies, optimal peptides for peptide receptor radionuclide targeting of CCK2/gastrin receptor-expressing tumours were the linear minigastrin analogue with six D-Glu residues (PP-F11), the divalent analogue MGD5 and the cyclic peptide cyclo-MG1. These peptides combined high tumour uptake with low kidney retention, and may therefore be good candidates for future clinical studies.
authors: Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, 6500 HB, Nijmegen, The Netherlands. p.laverman@nucmed.umcn.nl
authors: Peter
authors: P
authors: Laverman
authors: Lieke
authors: L
authors: Joosten
authors: Annemarie
authors: A
authors: Eek
authors: Susan
authors: S
authors: Roosenburg
authors: Petra Kolenc
authors: PK
authors: Peitl
authors: Theodosia
authors: T
authors: Maina
authors: Helmut
authors: H
authors: Mäcke
authors: Luigi
authors: L
authors: Aloj
authors: Elisabeth
authors: E
authors: von Guggenberg
authors: Jane K
authors: JK
authors: Sosabowski
authors: Marion
authors: M
authors: de Jong
authors: Jean-Claude
authors: JC
authors: Reubi
authors: Wim J G
authors: WJ
authors: Oyen
authors: Otto C
authors: OC
authors: Boerman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007205:Indium Radioisotopes / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D051379:Mice; D057054:Molecular Imaging; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics*; D011485:Protein Binding; D043887:Receptor, Cholecystokinin B / Q000378:metabolism*
chemical_list: D007205:Indium Radioisotopes; D010455:Peptides; D043887:Receptor, Cholecystokinin B