Biodistribution of Two Octreotate Analogs Radiolabeled with Indium and Yttrium in Rats (original) (raw)
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Anticancer research
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. 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 Wis...
Toxicity and dosimetry of 177Lu‐DOTA‐Y3‐octreotate in a rat model
… journal of cancer, 2001
Radiolabeled somatostatin analogs have demonstrated effectiveness for targeted radiotherapy of somatostatin receptor-positive tumors in both tumor-bearing rodent models and humans. A radionuclide of interest for cancer therapy is reactor-produced 177 Lu (t 1/2 = 6.64 d; β − [ ...
Radiopharmaceutical chemistry: Iodination techniques
The labeling of compounds with radioiodine has a long and varied history in biomedical research and the practice of nuclear medicine. In its simplest radiochemical form, sodium [ 131 I]iodide (t½ = 8.05 d) has had tremendous impact on the diagnostic evaluation of thyroid function in vivo as well as in the treatment of hyperthyroidism and thyroid cancer. Dramatic improvement in diagnostic image quality and marked reduction in patient absorbed radiation dose were achieved when 123 I (t½ = 13.3 h) was introduced into clinical practice. However, the application of any radioisotope of iodine is generally limited to the thyroid gland as long as the chemical form is restricted to the iodide (I -) anion.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1986
Iodine-125 (125I) and iodine-131- (131I) 6-iodocholest-5-en-3 beta-ol has been prepared directly from 6-chloromercuricholest-5-en-3 beta-ol and [125I] or [131I]sodium iodide. This method produces material of "no-carrier-added" specific activity and excellent radiochemical purity. The entire procedure is complete in 10 min and can be carried out in 95% ethanol. The biodistribution of this new high specific activity form of [131I]-6-iodocholest-5-en-3 beta-ol has been measured in rats and found to be very similar to that found for low specific activity [131I]-6-iodocholest-5-en-3 beta-ol produced by exchange labeling. The whole-body elimination curve over a 4-day period was measured and a dependence between the rate of elimination and specific activity was detected. Products of three different specific activities in addition to "no-carrier-added" material were studied.
Reduction of Renal Uptake of Radiolabeled Octreotate by Amifostine Coadministration
Journal of Nuclear Medicine, 2012
Megalin-mediated renal retention of radiolabeled somatostatin analogs may lead to nephrotoxicity during peptide receptor radionuclide therapy (PRRT). The cytoprotective agent amifostine protected rats from long-term nephrotoxicity after PRRT with 177 Lu-DOTA,Tyr 3-octreotate. This study describes the direct effect of amifostine on kidney and tumor uptake of 111 In-DOTA,Tyr 3-octreotate. Methods: In vivo biodistribution studies were performed using CA20948 tumor-bearing rats, with or without amifostine coadministration, via several routes. In vitro uptake was studied in somatostatin receptor-expressing CA20948 and megalin or cubilin receptor-expressing BN-16 cells, in the absence or presence of amifostine or its active metabolite WR-1065. Results: Coadministration of amifostine decreased renal uptake of radiolabeled octreotate in vivo, whereas tumor uptake was not affected. In agreement, amifostine and WR-1065 coincubation reduced uptake in BN-16 but not in CA20948 cells. Conclusion: Amifostine may provide renal protection during PRRT using somatostatin analogs, both by mitigation of radiation damage and the currently observed reduction of absorbed kidney radiation dose.
International Journal of Radiation Applications and Instrumentation. Part B. Nuclear Medicine and Biology, 1992
The influence of the ligands ethylenediaminetetramethylene phosphonic acid (EDTMP) and citrate (CIT) on the biodistribution of radio-yttrium in rats bearing a DS-carcinosarcoma was compared. '*Y-EDTMP and 87Y-CIT were i.v. injected into the same animals. Faster blood clearance and higher renal excretion were observed for the EDTMP-ligand. Of high practical interest is the reduced liver uptake of radio-yttrium (by one order of magnitude) with the EDTMP complex. Since bone and tumour accumulation is only weakly influenced, high tumour-to-liver ratios (up to 14) were observed. We propose to use EDTMP or similar complex ligands for liver blocking when radionuclides like wY, '-Yb, **$Ac or other group 3 elements are to be applied in endoradionuclide therapy technique.
Long-term toxicity of [177Lu-DOTA0,Tyr3]octreotate in rats
European Journal of Nuclear Medicine and Molecular Imaging, 2007
Purpose and methods: Studies on peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues have shown promising results with regard to tumour control. The efficacy of PRRT is limited by uptake and retention in the proximal tubules of the kidney, which might lead to radiation nephropathy. We investigated the long-term renal toxicity after different doses of [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate and the effects of dose fractionation and lysine co-injection in two tumourbearing rat models. Results: Significant renal toxicity was detected beyond 100 days after start of treatment as shown by elevated serum creatinine and proteinuria. Microscopically, tubules were strongly dilated with flat epithelium, containing protein cylinders. Creatinine levels rose significantly after 555 MBq [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate, but were significantly lower after 278 MBq (single injection) or two weekly doses of 278 MBq. Renal damage scores were maximal after 555 MBq and significantly lower in the 278 and 2×278 MBq groups. Three doses of 185 MBq [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate with intervals of a day, a week or a month significantly influenced serum creatinine (469±18, 134±70 and 65±15 μmol/l, respectively; p<0.001). Renal histological damage scores were not significantly influenced by dose fractionation. Lysine co-administration with three weekly treatments of 185 MBq significantly lowered serum creatinine and proteinuria. Conclusion: Injection of high doses of [ 177 Lu-DOTA 0 , Tyr 3 ]octreotate resulted in severe renal damage in rats as indicated by proteinuria, elevated serum creatinine and histological damage. This damage was dose dependent and became overt between 100 and 200 days after treatment. Dose fractionation had significant beneficial effects on kidney function. Also, lysine co-injection successfully prevented functional damage.
[177Lu-DOTA0,Tyr3]octreotate: comparison with [111In-DTPA0]octreotide in patients
European Journal of Nuclear Medicine, 2001
The somatostatin analogue [DOTA 0 ,Tyr 3 ]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA 0 , Tyr 3 ]octreotide. Also, labelled with the beta-and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [ 177 Lu-DOTA 0 ,Tyr 3 ]octreotate ( 177 Lu-octreotate) with [ 111 In-DTPA 0 ]octreotide ( 111 In-octreotide) in six patients with somatostatin receptor-positive tumours. Plasma radioactivity after 177 Luoctreotate expressed as a percentage of the injected dose was comparable with that after 111 In-octreotide. Urinary excretion of radioactivity was significantly lower than after 111 In-octreotide, averaging 64% after 24 h. The uptake after 24 h, expressed as a percentage of the injected dose of 177 Lu-octreotate, was comparable to that after 111 In-octreotide for kidneys, spleen and liver, but was three-to fourfold higher for four of five tumours. The spleen and kidneys received the highest absorbed doses. The doses to the kidneys were reduced by a mean of 47% after co-infusion of amino acids. It is concluded that in comparison with the radionuclide-coupled somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, 177 Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of 177 Lu as compared with 90 Y may be especially important for small tumours.
Current use and future potential of organometallic radiopharmaceuticals
European Journal of Nuclear Medicine and Molecular Imaging, 2002
Contrary to common belief, organometallic compounds exhibit remarkable stability in aerobic and even diluted aqueous solutions. Technetium-sestamibi (Cardiolite) is one of the most prominent examples of this class of compounds routinely used in nuclear medicine. This review summarises the recent progress in labelling of biomolecules with organometallic complexes for diagnostic and therapeutic application in radiopharmacy and exemplifies in detail developments focussing on organometallic technetium-and rhenium-tricarbonyl technologies. The value of such technologies has been recognised and they have become a valuable alternative to common labelling methodologies. An increasing number of groups have started to employ an organometallic precursor for the purpose of radioactive labelling of various classes of biomolecules, and the advantages and limitations of this new technique are compared with those of other labelling methods. The synthetic access to appropriate precursors via double-ligand exchange or aqueous carbonyl kit preparation for routine application is described. Strategies and examples for the design of appropriate bifunctional chelating agents for the Tc/Re-tricarbonyl core are given. The functionalisation of biomolecules such as tracers for the central nervous system (dopaminergic and serotonergic), tumour affine peptides (somatostatin receptors, neuroreceptors) and tumour binding single-chain antibody fragments is summarised. Where possible and appropriate, the in vitro and in vivo results in respect of these examples are compared with those obtained with classical 99m Tc/ 188 Re(V)-and 111 Inlabelled analogues. The preclinical results show the in many ways superior characteristics of organometallic labelling techniques.