title: Preclinical evaluation of new and highly potent analogues of octreotide for predictive imaging and targeted radiotherapy.
abstract: OBJECTIVE
  Molecular imaging and targeted radiotherapy are emerging fields in nuclear oncology. Five human somatostatin receptors (hsstr1-hsstr5) are known to be overexpressed to some degree on various tumors, sstr2 being the most important one. Clinically used somatostatin based radiopeptides target exclusively sstr2. The aim of this study was to develop novel analogues with a broader sstr profile for diagnostic (positron emission tomography and single-photon emission computed tomography) and radiotherapeutic applications.
  
  
  METHODS
  The following promising structures emerged from a parallel synthetic approach: [1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA(0)),1-Nal(3),Thr(8)]-octreotide (1, DOTA-NOC-ATE) and [DOTA(0),BzThi(3),Thr(8)]-octreotide (2, DOTA-BOC-ATE). The conjugates were labeled with cold and radioactive (111)In. Pharmacologic properties were compared with [(111)In-DOTA,Tyr(3)]-octreotide ([(111)In-DOTA]-TOC).
  
  
  RESULTS
  The receptor affinity profile showed high affinity of both peptides to hsstr2, hsstr3, and hsstr5 and some intermediate affinity to hsstr4, whereas [(111)In-DOTA]-TOC shows affinity only to sstr2. The internalization is fast in sstr2 expressing AR4-2J and in transfected sstr3 expressing human embryonic kidney 293 cells. Both radiopeptides internalize much more efficiently than [(111)In-DOTA]-TOC. Animal biodistribution studies showed very high and specific uptake of [(111)In]-1 and [(111)In]-2 in s.c. implanted AR4-2J tumors (Lewis rats) and in somatostatin receptor expressing normal tissues. The uptake was at least 2-fold higher in these tissues and in the tumor compared with [(111)In-DOTA]-TOC. In addition, the kidney uptake was significantly lower for both radiopeptides.
  
  
  CONCLUSIONS
  These data suggest that the novel radiopeptides are superior to [(111)In/(90)Y-DOTA]-TOC and show great promise for the clinical application in the imaging of somatostatin receptor-positive tumors and their targeted radiotherapy.
authors.affiliation: Division of Radiological Chemistry, Department of Radiology, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Ginj
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chen
authors.forename: Martin A
authors.initials: MA
authors.lastname: Walter
authors.forename: Veronique
authors.initials: V
authors.lastname: Eltschinger
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D004705:Endocytosis; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D008297:Male; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism / Q000532:radiotherapy; D015282:Octreotide / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D009942:Organometallic Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D051381:Rats; D011917:Rats, Inbred Lew; D017481:Receptors, Somatostatin / Q000378:metabolism; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: C580870:111In-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA(0)),1-Nal(3),Thr(8))octreotide; D018931:Antineoplastic Agents, Hormonal; D007205:Indium Radioisotopes; D009942:Organometallic Compounds; D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; C094573:somatostatin receptor 5; C093733:somatostatin receptor 2; D015282:Octreotide