BACKGROUND: Cholecystokinin receptor subtype 2 (CCK-2) is overexpressed in various tumours like medullary thyroid carcinomas and small cell lung cancer. Radiolabelled peptides that bind with high affinity and specificity to CCK-2 receptors, thus hold great potential for visualizing such tumours. METHODS: We compared four 111In labelled gastrin analogues, called minigastrins (MG), namely MG11, MG45, MG47 and MG48 linked to metal chelating DOTA in preclinical experiments. The radiolabelled peptides were tested for peptide binding in CCK-2 receptor-bearing cell line AR42J and for their pharmacokinetics in normal rats. RESULTS: The experiments suggest that all gastrin analogues had similar and relatively rapid internalization into AR42J cells. Binding to CCK-2 receptors in AR42J cells was saturable for all agents but there were some differences in receptor affinity. This biodistribution study in rats showed a rapid decrease in blood radioactivity, predominantly renal clearance and saturable uptake of the radiopharmaceutical and/or its metabolites in the CCK-2 receptor-positive stomach. Higher kidney accumulation of radioactivity was only found for 111In-DOTA-minigastrin 48. CONCLUSIONS: The data suggest that the 111In-DOTA-minigastrin analogues studied are promising candidates for the scintigraphy of CCK-2 receptor-expressing tumours; 111In-DOTA-MG47 and 111In-DOTA-MG11 are the most promising.
- MeSH
- Gastrins pharmacokinetics pharmacology MeSH
- Heterocyclic Compounds, 1-Ring MeSH
- Coordination Complexes MeSH
- Rats MeSH
- Cell Line, Tumor MeSH
- Peptides MeSH
- Radiopharmaceuticals MeSH
- Receptor, Cholecystokinin B metabolism MeSH
- Tissue Distribution MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- MeSH
- Biomedical Research MeSH
- Diagnostic Techniques, Radioisotope utilization MeSH
- Didelphis MeSH
- Financing, Organized MeSH
- Gastrins diagnostic use therapeutic use MeSH
- Isotope Labeling methods utilization MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Lutetium diagnostic use therapeutic use MeSH
- Cell Line, Tumor enzymology chemistry metabolism MeSH
- Pancreas, Exocrine cytology enzymology MeSH
- Kidney Tubules, Proximal cytology enzymology MeSH
- Indium Radioisotopes diagnostic use therapeutic use MeSH
- Receptor, Cholecystokinin B therapeutic use MeSH
- Spectrometry, Gamma methods utilization MeSH
- Statistics as Topic MeSH
- Technetium diagnostic use MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- Animals MeSH
- MeSH
- Financing, Organized MeSH
- Rats MeSH
- Kidney drug effects MeSH
- Octreotide analogs & derivatives diagnostic use MeSH
- Organometallic Compounds diagnostic use MeSH
- Cell Membrane Permeability drug effects MeSH
- Radiopharmaceuticals diagnostic use MeSH
- Radiotherapy methods utilization MeSH
- Receptors, Somatostatin metabolism drug effects MeSH
- Cell Separation utilization MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Abstracts MeSH
- MeSH
- Cell Culture Techniques methods utilization MeSH
- Financing, Organized MeSH
- Rats MeSH
- Cell Line, Tumor drug effects MeSH
- Pancreatic Neoplasms MeSH
- Octreotide analogs & derivatives pharmacology MeSH
- Receptors, Somatostatin drug effects MeSH
- Somatostatin analogs & derivatives MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Abstracts MeSH
OBJECTIVE: Radiolabeled receptor-specific somatostatin analogs labeled with gamma- or beta-emitting radionuclides are useful for scintigraphic imaging and/or therapy of selected neuroendocrine tumors. However, significant renal uptake may result in radiotoxicological injury of the kidney and can limit clinical application of the agents. The aim of the study was to analyze renal handling, rate, and mechanism of renal accumulation of two somatostatin receptor-targeted peptides, [DOTA(0), Tyr(3), Thr(8)]-octreotide (DOTA-TATE) and [DOTA(0), 1-Nal(3)]-octreotide (DOTA-NOC), labeled with indium-111 using in vitro methods. METHODS: The perfused rat kidney and freshly isolated rat renal cells were used as experimental models. The perfusion was performed in a recirculation regimen at constant pressure with solution containing bovine albumin, erythrocytes, and a mixture of essential substrates. The renal cells were isolated from rat kidneys using two-phase collagenase perfusion. Accumulation studies were used to evaluate the renal uptake of the peptides and to compare their accumulation with that of passively or actively transported model drugs. The influence of selected inhibitors of receptor-mediated endocytosis and the inhibition of energy-dependent transport processes on the uptake were also investigated using isolated renal cells. RESULTS: The renal clearance of (111)In-DOTA-NOC in the perfused rat kidney was significantly lower than that of (111)In-DOTA-TATE. Reverse situation was found in the case of renal retention. Pretreatment of the perfused kidney with maleate markedly decreased the renal retention. (111)In-DOTA-NOC was accumulated in the isolated renal cells at a higher rate than (111)In-DOTA-TATE (ratio 3: 1). The uptake of the radiopeptides in renal cells was higher than the uptake of not only the passively transported sucrose but also actively transported and accumulated methylglucose. The rank order of potency to inhibit the uptake by active endocytosis was approximately aprotinin > maleate > lysine. The uptake of the radiopeptides in the renal cells was temperature dependent. CONCLUSIONS: Both in vitro methods showed a higher renal accumulation of (111)In-DOTA-NOC in comparison with (111)In-DOTA-TATE. The renal uptake was partly decreased by inhibitors of receptor-mediated endocytosis and by a block of energy-dependent processes. A significant participation of active transport processes in renal accumulation of the studied peptides was confirmed.
- MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Kidney metabolism MeSH
- Metabolic Clearance Rate MeSH
- Octreotide analogs & derivatives diagnostic use pharmacokinetics MeSH
- Organometallic Compounds diagnostic use pharmacokinetics MeSH
- Rats, Wistar MeSH
- Radiopharmaceuticals diagnostic use pharmacokinetics MeSH
- Receptors, Somatostatin metabolism MeSH
- Reproducibility of Results MeSH
- Sensitivity and Specificity MeSH
- Tissue Distribution MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
BACKGROUND: In this study, some important biological characteristics of two radiolabelled somatostatin analogues 111In-DOTA-1-Nal3-octreotide (DOTA-NOC) and 111In-DOTA-Tyr3-octreotate (DOTA-TATE) were compared. MATERIALS AND METHODS: Rats were used for in vivo biodistribution experiments and in vitro cell models (OK and AR42J cell lines) were used for simulating the internalization in the kidney and in subtype 2 somatostatin receptor (SSTR2)-positive tissues, respectively. RESULTS: Significantly higher radioactivity concentrations in rat organs with high density of somatostatin receptors after 111In-DOTA-NOC administration in comparison with 111In-DOTA-TATE were observed. The predominant urine excretion was associated with accumulation of the radioactivity in the kidney, where higher retention of 111In-DOTA-TATE compared to 111In-DOTA-NOC was detected. In the OK cell line the opposite results were found. No significant differences in the in vitro internalization and externalization of radioactivity to AR42J cell line were found for either peptide suggesting their same affinity for SSTR2. CONCLUSION: Preclinical experiments indicated that 111In-DOTA-NOC is a very promising peptide for somatostatin receptor-positive tumour visualization. The conflict between the in vitro and in vivo kidney handling showed that the transfer of results from in vitro to in vivo conditions and their interpretation should be performed very carefully because both types of experiments can be affected by different factors, making their simple comparison difficult.
- MeSH
- Cell Line MeSH
- Financing, Organized MeSH
- Rats MeSH
- Kidney Tubules metabolism MeSH
- Cell Line, Tumor MeSH
- Pancreatic Neoplasms metabolism MeSH
- Octreotide analogs & derivatives pharmacokinetics chemistry MeSH
- Organometallic Compounds pharmacokinetics chemistry MeSH
- Rats, Wistar MeSH
- Radiopharmaceuticals pharmacokinetics MeSH
- Indium Radioisotopes MeSH
- Receptors, Somatostatin metabolism MeSH
- Tissue Distribution MeSH
- Opossums MeSH
- Chromatography, High Pressure Liquid MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Comparative Study MeSH
- MeSH
- Liver metabolism MeSH
- Rats MeSH
- Perfusion MeSH
- Radioactive Tracers pharmacokinetics chemistry MeSH
- Technetium Compounds pharmacokinetics chemistry MeSH
- Sulfobromophthalein pharmacokinetics MeSH
- Bile chemistry secretion MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Comparative Study MeSH
