title: Tetraamine-modified octreotide and octreotate: labeling with 99mTc and preclinical comparison in AR4-2J cells and AR4-2J tumor-bearing mice.
abstract: Two somatostatin analogues, [(99m)Tc]Demotide and [(99m)Tc]Demotate 4, were compared with [(99m)Tc]Demotate 1, a previously reported somatostatin receptor subtype 2 (sst(2)) targeting tracer. Conjugates were prepared by coupling an open-chain tetraamine chelator to D-Phe(1) of [Tyr(3)]-octreotide or [Tyr(3)]-octreotate, respectively, via a p-benzylaminodiglycolic acid spacer adopting solid-phase peptide synthesis techniques. Peptide conjugates were collected in a highly pure form after chromatographic purification. Eventually, [(99m)Tc]Demotide and [(99m)Tc]Demotate 4 were obtained in approximately 1 Ci/micromol specific activity and >96% purity after labeling under alkaline conditions. Demotide and Demotate 4 exhibited similar high binding affinities for the sst(2) expressed in AR4-2J cells with IC(50) values 0.16 and 0.10 nM, respectively. The (radio)metallated analogues [(99m)Tc]Demotide and [(99m)Tc]Demotate 4 showed equally high affinities to the sst(2) during saturation binding assays in AR4-2J cell membranes (K(d)s 0.08 and 0.07 nM, respectively). During incubation at 37 degrees C with AR4-2J cells, the radiopeptides internalized effectively via a receptor-mediated process, with [(99m)Tc]Demotate 4 exhibiting a faster internalization rate than [(99m)Tc]Demotide. After injection in athymic mice bearing sst(2)-expressing AR4-2J tumors, the radiotracers showed high and specific uptake in the tumor (>25%ID/g at 1 h) and in the sst(2)-positive organs. However, both [(99m)Tc]Demotide and [(99m)Tc]Demotate 4 showed unfavorably higher background activity, especially in the abdomen, in comparison to [(99m)Tc]Demotate 1 and are, therefore, less suited than [(99m)Tc]Demotate 1 for sst(2)-targeted tumor imaging in man.
authors.affiliation: Institute of Radioisotopes-Radiodiagnostic Products, National Center for Scientific Research Demokritos, 153 10 Athens, Greece.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nikolopoulou
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
authors.forename: Petros
authors.initials: P
authors.lastname: Sotiriou
authors.forename: Paul
authors.initials: P
authors.lastname: Cordopatis
authors.forename: Berthold A
authors.initials: BA
authors.lastname: Nock
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D051379:Mice; D015282:Octreotide / Q000737:chemistry* / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D010190:Pancreatic Neoplasms / Q000737:chemistry* / Q000000981:diagnostic imaging / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000493:pharmacokinetics; D011877:Radionuclide Imaging; D051381:Rats; D014018:Tissue Distribution
chemical_list: D000588:Amines; D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; C470036:octreotate, Tyr(3)-; D015282:Octreotide