title: Impact of dianionic and dicationic linkers on tumor uptake and biodistribution of [64Cu]Cu/NOTA peptide-based gastrin-releasing peptide receptors antagonists.
abstract: In this study, we investigated for the first time the influence of 2-aminoethyl-piperazine-1-carboxylic acid (APCA) and amino-hexanedioic-1-acid (AHDA) on tumor uptake and elimination kinetics of [64Cu]-radiolabeled gastrin releasing peptide receptors (GRPR) antagonists. Three GRPR antagonists containing the RM26 sequence were synthesized and conjugated with NOTA via different linkers (LK): polyethylene glycol (PEG-neutral), APCA (dicationic) or AHDA (dianionic). The NOTA-LK-RM26 peptides were radiolabeled with64Cu to assess their pharmacokinetic and positron emission tomography (PET) imaging properties using PC3 tumor-bearing athymic nude mice. The inhibition constants (Ki) of the 3natCu/NOTA-LK-RM26 peptides bearing PEG, dicationic and dianionic linkers were 0.98 ± 0.48 nM, 0.95 ± 0.21 nM, and 17.97 ± 2.79 nM, respectively. The [64Cu] NOTA-LK-RM26 conjugates were prepared with labeling yields superior to 95% and specific activities of 67 to 77 TBq/mmol. The 3 radiopeptides were stable in vivo and showed GRPR-specific uptake in pancreas with a very fast washout of this tissue observed for [64Cu]-NOTA-AHDA-RM26 peptide. Results from imaging studies displayed specific PC3 tumor uptake for both [64Cu]-NOTA-APCA- and AHDA-RM26, similar kidney elimination and fast liver washout. Considering their adequate imaging characteristics, [64Cu]-NOTA-LK-RM26 bearing APCA- and AHDA-linkers are promising candidates for GRPR-targeted PET imaging prostate cancer.
authors.affiliation: Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Sherbrooke Molecular Imaging Centre, Centre de recherche du CHUS (CRCHUS), Sherbrooke, Canada.
authors.forename: Nematallah
authors.initials: N
authors.lastname: Mansour
authors.affiliation: Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Sherbrooke Molecular Imaging Centre, Centre de recherche du CHUS (CRCHUS), Sherbrooke, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dumulon-Perreault
authors.affiliation: Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Sherbrooke Molecular Imaging Centre, Centre de recherche du CHUS (CRCHUS), Sherbrooke, Canada.
authors.forename: Samia
authors.initials: S
authors.lastname: Ait-Mohand
authors.affiliation: Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Sherbrooke Molecular Imaging Centre, Centre de recherche du CHUS (CRCHUS), Sherbrooke, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Paquette
authors.affiliation: Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Sherbrooke Molecular Imaging Centre, Centre de recherche du CHUS (CRCHUS), Sherbrooke, Canada.
authors.forename: Roger
authors.initials: R
authors.lastname: Lecomte
authors.affiliation: Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Sherbrooke Molecular Imaging Centre, Centre de recherche du CHUS (CRCHUS), Sherbrooke, Canada.
authors.forename: Brigitte
authors.identifier: 0000-0002-0319-4512
authors.initials: B
authors.lastname: Guérin
mesh_terms: D015074:2-Aminoadipic Acid / Q000737:chemistry*; D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D010879:Piperazines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D049268:Positron-Emission Tomography; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C000625005:2-aminoethylpiperazine-1-carboxylic acid; D003301:Copper Radioisotopes; D006571:Heterocyclic Compounds; D006573:Heterocyclic Compounds, 1-Ring; D010455:Peptides; D010879:Piperazines; D018004:Receptors, Bombesin; D015074:2-Aminoadipic Acid; D011092:Polyethylene Glycols; C048993:1,4,7-triazacyclononane-N,N',N''-triacetic acid
keywords: 64Cu-NOTA-RM26; Gastrin releasing peptide receptors; PC3 tumor; charged linker; prostate cancer