title: DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours.
abstract: OBJECTIVE
  We aimed at designing and developing a novel bombesin analogue, DOTA-PEG(4)-BN(7-14) (DOTA-PESIN), with the goal of labelling it with (67/68)Ga and (177)Lu for diagnosis and radionuclide therapy of prostate and other human cancers overexpressing bombesin receptors.
  
  
  METHODS
  The 8-amino acid peptide bombesin (7-14) was coupled to the macrocyclic chelator DOTA via the spacer 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG(4)). The conjugate was complexed with Ga(III) and Lu(III) salts. The GRP receptor affinity and the bombesin receptor subtype profile were determined in human tumour specimens expressing the three bombesin receptor subtypes. Internalisation and efflux studies were performed with the human GRP receptor cell line PC-3. Xenografted nude mice were used for biodistribution.
  
  
  RESULTS
  [Ga(III)/Lu(III)]-DOTA-PESIN showed good affinity to GRP and neuromedin B receptors but no affinity to BB3. [(67)Ga/(177)Lu]-DOTA-PESIN internalised rapidly into PC-3 cells whereas the efflux from PC-3 cells was relatively slow. In vivo experiments showed a high and specific tumour uptake and good retention of [(67)Ga/(177)Lu]-DOTA-PESIN. [(67)Ga/(177)Lu]-DOTA-PESIN highly accumulated in GRP receptor-expressing mouse pancreas. The uptake specificity was demonstrated by blocking tumour uptake and pancreas uptake. Fast clearance was found from blood and all non-target organs except the kidneys. High tumour-to-normal tissue ratios were achieved, which increased with time. PET imaging with [(68)Ga]-DOTA-PESIN was successful in visualising the tumour at 1 h post injection. Planar scintigraphic imaging showed that the (177)Lu-labelled peptide remained in the tumour even 3 days post injection.
  
  
  CONCLUSIONS
  The newly designed ligands have high potential with regard to PET and SPECT imaging with (68/67)Ga and targeted radionuclide therapy with (177)Lu.
authors.affiliation: Division of Radiological Chemistry, Department of Radiology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Zhang
authors.forename: Jochen
authors.initials: J
authors.lastname: Schuhmacher
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.forename: Damian
authors.initials: D
authors.lastname: Wild
authors.forename: Michael
authors.initials: M
authors.lastname: Eisenhut
authors.forename: Jean Claude
authors.initials: JC
authors.lastname: Reubi
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000737:chemistry; D045744:Cell Line, Tumor; D005710:Gallium Radioisotopes; D015972:Gene Expression Regulation, Neoplastic; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D008187:Lutetium; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D011868:Radioisotopes; D011877:Radionuclide Imaging / Q000379:methods; D018004:Receptors, Bombesin / Q000096:biosynthesis*
chemical_list: C525059:DOTA-PEG(4)-bombesin (7-14); D005710:Gallium Radioisotopes; D006573:Heterocyclic Compounds, 1-Ring; D011868:Radioisotopes; D018004:Receptors, Bombesin; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D008187:Lutetium; D001839:Bombesin