Polyamidoamine dendrimers (PAMAMs) of generations 1 (G1) and 4 (G4) were conjugated with a bifunctional pyridine-N-oxide DOTA analog, 10-[(4-carboxy-1-oxidopyridin-2-yl)methyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (H(4)do3a-py(NO-C)), through the pyridine-4-carboxylic acid group, and the conjugates were radiolabeled with indium-111. Reaction conditions for the radiolabelling were optimized. Both radiolabeled conjugates, G1-[(111)In(do3a-py(NO-C))] and G4-[(111)In(do3a-py(NO-C))], were kinetically stable for at least 48h after preparation; in the presence of competitive ligands, the radiochemical purity of the conjugates slightly decreased (4-7%) over the same time period. The preclinical pharmacokinetics of both agents were evaluated. Biodistribution and elimination in rats were more favorable for the G1-[(111)In(do3a-py(NO-C))] conjugate than G4-[(111)In(do3a-py(NO-C))] conjugate. However, the G1-[(111)In(do3a-py(NO-C))] conjugate was rapidly eliminated from the body, mainly through urine, while, significant and long-term radioactivity uptake in the liver and kidney was observed for the G4-[(111)In(do3a-py(NO-C))] conjugate.
- MeSH
- dendrimery chemie farmakokinetika MeSH
- heterocyklické sloučeniny monocyklické chemie farmakokinetika MeSH
- izotopové značení metody MeSH
- krysa rodu rattus MeSH
- nosiče léků chemie farmakokinetika MeSH
- potkani Wistar MeSH
- pyridiny chemie farmakokinetika MeSH
- radiofarmaka chemie farmakokinetika MeSH
- radioizotopy india chemie farmakokinetika MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Three different procedures for the labeling of hyaluronan (HA) with (111)In, (125)I and (14)C radionuclides were compared, and the kinetic stability of radiolabeled HA under different conditions (saline, artificial gastric juice and plasma) was established. Modification of HA structure with bifunctional chelating agents (DTPA) or with the prosthetic group (tyramine or tyrosine) was essential prior (111)In and (125)I labeling. These chemical labeling techniques were fast, simple and inexpensive, and labeled agents with a high specific activity were obtained. The only disadvantage of these methods was the occurrence of unknown functional groups in the HA molecule requiring further characterization of the compound. Conversely, HA labeling with (14)C by biotechnological synthesis was found to be rather expensive and time-consuming process. Although, the final product (14)C-HA was identical to natural HA its low specific activity presents certain limitation for its application in biological experiments. Stability studies showed that (14)C-HA and (125)I-Tm-HA were stable in all studied mediums. In the case of (125)I-Trs-HA, stability slightly decreased in rat plasma and in artificial gastric juice with increasing time. The least stable was (111)In-DTPA-HA, which degraded completely after 48h in artificial gastric juice. Kinetic stability studies may provide primary information concerning the properties of radiolabeled HA in vitro, which is essential for the use and explanation of its behavior in biological experiments.
- MeSH
- krysa rodu rattus MeSH
- kyselina hyaluronová chemická syntéza farmakokinetika MeSH
- potkani Wistar MeSH
- radioizotopy india chemie farmakokinetika MeSH
- radioizotopy jodu chemie farmakokinetika MeSH
- radioizotopy uhlíku chemie farmakokinetika MeSH
- stabilita léku MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
BACKGROUND: Somatostatin analogues labelled with radiometals or radiohalogens are useful for the imaging and treatment of somatostatin receptor-containing tumours. In this study, the procedures for the radioiodination of glucose-Tyr3-octreotate (gluc-Tyr3-tate) and radiolabelling of DOTA-Tyr3-octreotate (DOTA-Tyr3-tate) with 111In, 177Lu and 125I were compared and their metabolism in rats was analyzed. The usefulness of high performance liquid chromatography (HPLC) analysis and instant thin-layer chromatography on silica gel (ITLC-SG) for both radiochemical purity determination and analysis of metabolism in urine was investigated. MATERIALS AND METHODs: For labelling with radiometals, the formation of a complex with the 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) functionality of the peptide was employed. Radioiodination was performed by the chloramime-T method. The radiochemical purity of radiolabelled peptides and the analyses of rat urine were determined by HPLC and/or ITLC-SG methods. Male Wistar rats were used in the elimination studies. RESULTS: DOTA-Tyr3-tate was simply radiolabelled with radiometals with high yield and high radiochemical purity. Stopping of the reaction was a critical step for radioiodination, therefore labelling of gluc-Tyr3-tate and DOTA-Tyr3-tate with 125I was not so simple and the reaction product had to be purified by preparative HPLC analysis. Whereas 111In-DOTA-Tyr3-tate and 177Lu-DOTA-Tyr3-tate were eliminated in rat urine in a practically unchanged form, a significant proportion of metabolites was observed with radioiodinated peptides, particularly at longer time intervals. CONCLUSION: Labelling of DOTA-Tyr3-tate with radiometals is simple and the radiochemical purity of prepared compounds is very high, while iodination of the peptides demands purification of the product by preparative HPLC. The analysis of rat urine showed that excretion of radioiodinated peptides included a significant proportion of metabolites.
- MeSH
- cyklické peptidy chemie metabolismus MeSH
- financování organizované MeSH
- glukosa analogy a deriváty metabolismus MeSH
- heterocyklické sloučeniny monocyklické chemie metabolismus MeSH
- izotopové značení MeSH
- krevní proteiny metabolismus MeSH
- krysa rodu rattus MeSH
- lutecium chemie MeSH
- potkani Wistar MeSH
- radiofarmaka chemická syntéza metabolismus MeSH
- radioizotopy india chemie MeSH
- radioizotopy jodu chemie MeSH
- radionuklidy chemie MeSH
- vazba proteinů MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
