title: [99mTc]Demotate, a new 99mTc-based [Tyr3]octreotate analogue for the detection of somatostatin receptor-positive tumours: synthesis and preclinical results.
abstract: Demotate is a new tetraamine-functionalised [Tyr3]octreotate derivative that binds technetium-99m with a high efficiency under mild conditions. The resulting radioligand, [99mTc]Demotate, forms in a high purity and is stable for at least 6 h after labelling. The affinity of the unlabelled peptide for somatostatin receptors is high (IC(50)=0.13 n M) and comparable to that of [Tyr3]octreotate or [Tyr3]octreotide, as demonstrated by competition binding experiments in rat brain cortex or AR42J cell membrane preparations. An equally very high affinity ( K(d)=0.07 n M) was exhibited by [99mTc/99gTc]Demotate during saturation binding experiments using rat brain cortex membrane homogenates. The radioligand resisted hydrolytic degradation in mouse plasma and was excreted intact in mouse urine. In vivo, [99mTc]Demotate cleared very rapidly from non-target tissues into the bladder via the kidneys, while radioactivity uptake in target organs was very high. In mice bearing the experimental AR42J tumour, [99mTc]Demotate demonstrated a very high tumour uptake at 1 h p.i. (25%ID/g) that remained high (20%ID/g) at 4 h p.i. This uptake could be effectively blocked by co-injection of a high dose of [Tyr3]octreotate together with the radioligand. High-quality planar and single-photon emission tomographic images were acquired 1 h after injection of [99mTc]Demotate in tumour-bearing mice, illustrating the excellent properties of this agent for somatostatin receptor tumour imaging.
authors.affiliation: Institute of Radioisotopes - Radiodiagnostic Products, National Center for Scientific Research Demokritos, 15310 Ag. Paraskevi, Attikis, Athens, Greece. mainathe@mail.demokritos.gr
authors.forename: Theodosia
authors.initials: T
authors.lastname: Maina
authors.forename: Berthold
authors.initials: B
authors.lastname: Nock
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nikolopoulou
authors.forename: Petros
authors.initials: P
authors.lastname: Sotiriou
authors.forename: George
authors.initials: G
authors.lastname: Loudos
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Maintas
authors.forename: Paul
authors.initials: P
authors.lastname: Cordopatis
authors.forename: Efstratios
authors.initials: E
authors.lastname: Chiotellis
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007553:Isotope Labeling / Q000379:methods*; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D015282:Octreotide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011485:Protein Binding; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D015609:Organotechnetium Compounds; D010456:Peptides, Cyclic; D017481:Receptors, Somatostatin; C470036:octreotate, Tyr(3)-; C114933:octreotide, iodoTyr(3)-; C470035:technetium Tc 99m demotate; C045210:3-Tyr-octreotide; C093733:somatostatin receptor 2; D015282:Octreotide