title: Copper-64 Labeled Macrobicyclic Sarcophagine Coupled to a GRP Receptor Antagonist Shows Great Promise for PET Imaging of Prostate Cancer.
abstract: The gastrin-releasing peptide receptor (GRPr) is an important molecular target for the visualization and therapy of tumors and can be targeted with radiolabeled bombesin derivatives. The present study aims to develop statine-based bombesin receptor antagonists suitable for labeling with 64Cu for imaging by positron emission tomography (PET). The potent GRPr antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 was conjugated to the sarcophagine (3,6,10,13,16,19-hexaazabicyclo[6.6.6] icosane=Sar) derivative 5-(8-methyl-3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar) via PEG4 (LE1) and PEG2 (LE2) spacers and radiolabeled with 64Cu2+ with >95% yield and specific activities of about 100 MBq/nmol. Both Cu(II) conjugates have high affinity for GRPr (IC50: natCu-LE1, 1.4±0.1 nM; natCu-LE2, 3.8±0.6 nM). The antagonistic properties of both conjugates were confirmed by Ca2+-flux measurements. Biodistribution studies of Cu-64-LE1 exhibited specific targeting of the tumor (19.6±4.7% IA/g at 1 h p.i.) and GRPr-positive organs. Biodistribution and PET images at 4 and 24 h postinjection showed increasing tumor-to-background ratios with time. This was illustrated by the acquisition of PET images showing high tumor-to-normal tissue contrast. This study demonstrates the high affinity of the MeCOSar-PEGx-bombesin conjugates to GRPr. The stability of 64Cu complexes of MeCOSar, the long half-life of 64Cu, and the suitable biodistribution profile of the 64Cu-labeled peptides lead to PET images of high contrast suitable for potential translation into the clinic.
authors.affiliation: †German Cancer Consortium (DKTK), Heidelberg 69120, Germany.|‡Department of Nuclear Medicine, University Hospital Freiburg, Freiburg 79106, Germany.|§German Cancer Research Center (DKFZ), Heidelberg 69121, Germany.
authors.forename: Eleni
authors.initials: E
authors.lastname: Gourni
authors.affiliation: ‡Department of Nuclear Medicine, University Hospital Freiburg, Freiburg 79106, Germany.
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Pozzo
authors.affiliation: ‡Department of Nuclear Medicine, University Hospital Freiburg, Freiburg 79106, Germany.
authors.forename: Emilie
authors.initials: E
authors.lastname: Kheirallah
authors.affiliation: ∥3B Pharmaceuticals, Berlin 12489, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Smerling
authors.affiliation: ⊥Department of Pathology, University Hospital Bern, Bern 3010, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waser
authors.affiliation: ⊥Department of Pathology, University Hospital Bern, Bern 3010, Switzerland.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Reubi
authors.affiliation: #School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Paterson
authors.affiliation: #School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
authors.affiliation: ‡Department of Nuclear Medicine, University Hospital Freiburg, Freiburg 79106, Germany.
authors.forename: Philipp T
authors.initials: PT
authors.lastname: Meyer
authors.affiliation: ‡Department of Nuclear Medicine, University Hospital Freiburg, Freiburg 79106, Germany.
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Maecke
mesh_terms: D000818:Animals; D003301:Copper Radioisotopes / Q000493:pharmacokinetics*; D004151:Dipeptides / Q000737:chemistry*; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010446:Peptide Fragments / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D003301:Copper Radioisotopes; D004151:Dipeptides; D006571:Heterocyclic Compounds; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; C016968:alanyltyrosine
keywords: 64Cu; PET-imaging; gastrin-releasing peptide receptor antagonists; sarcophagine MeCOSar chelator