title: New pansomatostatin ligands and their chelated versions: affinity profile, agonist activity, internalization, and tumor targeting.
abstract: OBJECTIVE
  Somatostatin receptor (sst) targeting is an established method to image and treat sst-positive tumors. Particularly, neuroendocrine tumors express the receptor subtype 2 in high density, but sst1, sst3, sst4, and sst5 are also expressed to some extent in different human tumors. Currently used targeting peptides mainly have sst2 affinity. We aimed at developing (radio)peptides that bind with high affinity to all receptor subtypes.
  
  
  METHODS
  Carbocyclic octapeptides were coupled with macrocyclic chelators for radiometal labeling. Affinity, internalization, and agonist potencies were determined on sst1- to sst5-expressing cell lines. Biodistribution was determined on nude mice bearing HEK-sst2 or AR4-2J and HEK-sst3 tumors.
  
  
  RESULTS
  High affinity to all receptor subtypes was found. Y(III)-KE88 showed agonistic properties at all five sst receptor subtypes as it inhibits forskolin-stimulated cyclic AMP production. Surprisingly, very low or even absent sst2 receptor internalization was found compared with currently clinically established octapeptides, whereas the sst3 internalization was very efficient. Biodistribution studies of [(111)In]KE88 and [(67)Ga]KE88/[(68)Ga]KE88 reflected the in vitro data. In nude mice with s.c. implanted sst2 (HEK-sst2, AR4-2J)-expressing and sst3 (HEK-sst3)-expressing tumors, high and persistent uptake was found in sst3-expressing tumors, whereas the uptake in the sst2-expressing tumors was lower and showed fast washout. The kidney uptake was high but blockable by coinjection of lysine.
  
  
  CONCLUSIONS
  This peptide family shows pansomatostatin potency. As radiopeptides, they are the first to show a full pansomatostatin profile. Despite some drawback, they should be useful for imaging sst2-expressing tumors with short-lived radiometals, such as (68)Ga, at early time points and for sst3-expressing tumors at later time points with longer-lived radiometals, such as (64)Cu or (86)Y.
authors.affiliation: Division of Radiological Chemistry, University Hospital Basel, Basel, Switzerland.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Ginj
authors.forename: Hanwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Eisenwiener
authors.forename: Damian
authors.initials: D
authors.lastname: Wild
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulz
authors.forename: Hans
authors.initials: H
authors.lastname: Rink
authors.forename: Renzo
authors.initials: R
authors.lastname: Cescato
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D002846:Chromatography, Affinity; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000000981:diagnostic imaging; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding / Q000502:physiology; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics; D011869:Radioligand Assay; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism; D013004:Somatostatin / Q000737:chemistry* / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D008024:Ligands; D010455:Peptides; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D017481:Receptors, Somatostatin; D013004:Somatostatin