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1.
J Nucl Med ; 49(9): 1506-11, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18703613

ABSTRACT

UNLABELLED: In most types of peptide receptor radionuclide therapy, the maximum activity dose that can be administered is limited by high and persistent renal retention of the radiolabeled peptides, which is, at least partly, mediated by the megalin receptor. Several agents that interfere with renal reabsorption of radiolabeled peptides have been identified (e.g., lysine, arginine, succinylated gelatin solution), but none of these inhibit renal reabsorption completely. Albumin, a naturally abundant megalin ligand, might be a safe and potent alternative. In this study, we analyzed the effects of albumin and fragments of albumin (FRALB) on the renal reabsorption of (111)In-diethylenetriaminepentaacetic acid (DTPA)-d-Phe(1)-octreotide ((111)In-octreotide), [Lys(40)(aminohexoic acid-DTPA-(111)In)NH(2)]-exendin-4 ((111)In-exendin), and (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-Glu(1)-minigastrin ((111)In-minigastrin). METHODS: The effects of albumin and FRALB on megalin-associated binding of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin were assessed in vitro using rat yolk sac epithelial (BN16) cells. In vivo, uptake and localization of (111)In-albumin and (111)In-FRALB in the kidneys of Wistar rats were determined, as well as the effect of lysine, succinylated gelatin solution, albumin, and FRALB on the kidney uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin. RESULTS: FRALB significantly reduced binding and uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin by BN16 cells. In rats, renal uptake of (111)In-labeled FRALB was significantly higher than that of (111)In-labeled intact albumin (P<0.001). FRALB administration effectively reduced renal uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin. Administration of 1-2 mg of FRALB reduced renal uptake of (111)In-octreotide as efficiently as 80 mg of lysine. CONCLUSION: Renal uptake of (111)In-octreotide and other radiolabeled peptides in rats can be effectively reduced by administration of albumin fragments. Additional studies to identify the albumin fragments responsible for inhibition of renal peptide uptake are warranted.


Subject(s)
Kidney/metabolism , Low Density Lipoprotein Receptor-Related Protein-2/metabolism , Peptides/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Serum Albumin/pharmacokinetics , Animals , Isotope Labeling , Kidney/diagnostic imaging , Male , Metabolic Clearance Rate , Peptide Fragments/pharmacokinetics , Radionuclide Imaging , Rats , Rats, Wistar , Tissue Distribution
2.
Nucl Med Biol ; 34(6): 691-5, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17707809

ABSTRACT

UNLABELLED: It was previously shown that the (99m)Tc-labeled hydrazinonicotinamide (HYNIC)-conjugated LTB4 antagonist MB81 visualized infectious foci in rabbits adequately and within a few hours after injection. Here, the bivalent HYNIC-conjugated LTB4 antagonist MB67 (analog of MB81) was fluorinated with (18)F via hydrazone formation and tested in vivo. METHODS: MB67 was [(18)F]-fluorinated via reaction of the [(18)F]-fluorinated intermediate p-[(18)F]-fluorobenzaldehyde ([(18)F]FB) and the HYNIC moiety of MB67 via hydrazone formation. For comparison, MB67 was also labeled with (99m)Tc. The biodistribution of (18)F- and (99m)Tc-labeled MB67 was investigated in rabbits with intramuscular infection. RESULTS: [(18)F]-MB67 was obtained at a maximum specific activity of 1200 GBq/mmol and proved to be stable in phosphate buffered saline (PBS) at 37 degrees C for at least 4 h. PET images obtained with [(18)F]-MB67 clearly delineated the abscess at 2 and 4 h pi. Counting of dissected tissues at 4 h pi revealed an abscess uptake of 0.073+/-0.005 %ID/g, as compared to 0.160+/-0.010 %ID/g for the (99m)Tc-labeled analog. Abscess-to-muscle ratios were 23+/-4 for [(18)F]-MB67 and 35+/-9 for [(99m)Tc]-MB67. CONCLUSION: The present study showed the feasibility of a new [(18)F]-labeling methodology and its application in the production of a new PET tracer for imaging of infection, [(18)F]-MB67.


Subject(s)
Hydrazines , Infections/diagnostic imaging , Leukotriene B4/antagonists & inhibitors , Niacinamide/analogs & derivatives , Radiopharmaceuticals/chemical synthesis , Abscess/diagnostic imaging , Animals , Escherichia coli Infections/diagnostic imaging , Fluorine Radioisotopes/chemistry , Hydrazones/chemical synthesis , Indicators and Reagents , Isotope Labeling , Muscular Diseases/diagnostic imaging , Positron-Emission Tomography , Rabbits , Radiopharmaceuticals/pharmacokinetics , Technetium/chemistry , Tissue Distribution
3.
Ann Surg Oncol ; 14(2): 533-40, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17122992

ABSTRACT

BACKGROUND: Treatment of patients with peritoneal carcinomatosis (PC) of colorectal cancer (CRC) includes cytoreductive surgery (CS) in combination with (hyperthermic) intraperitoneal chemotherapy (HIPEC), resulting in a limited survival benefit with high morbidity and mortality rates. Radioimmunotherapy (RIT) as adjuvant therapy after CS of CRC has been shown to prolong survival in preclinical studies. However, the optimal setting of RIT remains to be determined. METHODS: PC was induced by intraperitoneal inoculation of CC-531 colon carcinoma cells in Wag/Rij rats. Animals were subjected to exploratory laparotomy (Sham), CS only or CS + RIT at different time points after surgery. RIT consisted of 55 MBq lutetium-177-labelled anti-CC531 antibody MG1 (183 mug). The primary endpoint was survival. RESULTS: Cytoreductive surgery with or without RIT was well tolerated. Median survival of animals in the Sham and CS group was 29 days and 39 days, respectively (P < 0.04). Compared to CS alone, median survival of rats after adjuvant RIT was 77 days (P < 0.0001), 52 days (P < 0.0001) and 45 days (P < 0.0001) when given directly, 4 and 14 days after surgery, respectively. CONCLUSION: The efficacy of adjuvant RIT after CS for the treatment of PC of colonic origin decreases when the administration of the radiolabelled MAbs is postponed. This study shows that adjuvant RIT should be given as early as possible after surgery.


Subject(s)
Colorectal Neoplasms/radiotherapy , Peritoneal Neoplasms/radiotherapy , Radioimmunotherapy , Radiotherapy, Adjuvant , Animals , Colorectal Neoplasms/pathology , Colorectal Neoplasms/surgery , Combined Modality Therapy , Disease Models, Animal , Infusions, Parenteral , Male , Neoplasms, Experimental , Peritoneal Neoplasms/secondary , Peritoneal Neoplasms/surgery , Peritoneum , Rats , Rats, Inbred Strains , Time Factors , Treatment Outcome
4.
Eur J Nucl Med Mol Imaging ; 33(11): 1266-72, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16832635

ABSTRACT

PURPOSE: P-glycoprotein (P-gp) is a membrane efflux pump protein that is involved in multidrug resistance (MDR). Tumour cells with high P-gp expression show poor response to cancer treatment with several chemotherapeutics. In vivo targeting and visualisation of P-gp expression would allow MDR to be evaluated non-invasively prior to treatment. The aim of this study was to investigate the feasibility of visualising P-gp expression in tumours using a monoclonal anti-P-gp antibody, 15D3. METHODS: Nude BALB/c mice with subcutaneously growing human uterine sarcoma cell tumours with either high (MES-SA/Dx5 1977) or low (MES-SA 1976) P-gp expression were used. When tumours were 0.2-0.4 g, mice received (131)I-15D3 or (111)In-DTPA-15D3 monoclonal anti-P-gp antibody intravenously. Images were acquired up to 3 days p.i. and radioactivity concentration in various tissues was determined after euthanisation of the animals. RESULTS: The images demonstrated that radioactivity accumulated to a higher concentration in high P-gp expressing tumours than in the low P-gp expressing MES-SA 1976 tumour. Furthermore, visualisation of the P-gp expressing tumours was superior with (111)In-DTPA-15D3 than with (131)I-15D3. After injection of (111)In-DTPA-15D3, the high P-gp expressing MES-SA/Dx5 1977 tumours were clearly visualised at 3 days p.i. The biodistribution data indicated that radioactivity concentration in the high P-gp expressing tumours was higher than in the tumours with low P-gp expression (20.78+/-1.42 %ID/g for MES-SA/Dx5 1977 tumours and 8.39+/-3.78 %ID/g for MES-SA 1976 tumours for (111)In-DTPA-15D3). CONCLUSION: The (111)In-labelled monoclonal anti-P-gp antibody clearly visualised P-gp expression in a human uterine sarcoma tumour in nude mice.


Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antibodies, Monoclonal/pharmacokinetics , Uterine Neoplasms/diagnostic imaging , Uterine Neoplasms/metabolism , Animals , Feasibility Studies , Female , Gene Expression Profiling/methods , Indium Radioisotopes/pharmacokinetics , Mice , Mice, Inbred BALB C , Mice, Nude , Radionuclide Imaging , Reproducibility of Results , Sensitivity and Specificity , Tissue Distribution
5.
J Nucl Med ; 47(3): 528-33, 2006 Mar.
Article in English | MEDLINE | ID: mdl-16513623

ABSTRACT

UNLABELLED: 111In-Diethylenetriaminepentaacetic acid-octreotide generally is used for the scintigraphic imaging of neuroendocrine and other somatostatin receptor-positive tumors. On the basis of the successful targeting of octreotide, radiolabeled somatostatin analogs, such as 90Y-(1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid [DOTA])0-Tyr3-octreotide and 177Lu-DOTA0-Tyr3-octreotate, were developed for peptide receptor radionuclide therapy. However, the maximum tolerated doses of these analogs are limited because of the high and persistent renal uptake that leads to relatively high radiation doses in the kidneys. Renal uptake can be reduced by coinfusion of basic amino acids or polypeptides. However, high doses of basic amino acids can induce severe side effects. It was reported that the infusion of gelatin-based plasma expanders resulted in increased low-molecular-weight proteinuria, suggesting that these plasma expanders interfere with the tubular reabsorption of peptides and proteins. In the present study, we analyzed the effects of several plasma expanders on the renal uptake of 111In-octreotide in rats and mice. METHODS: Wistar rats and BALB/c mice were injected with 0.5 or 0.1 mL of plasma expander, respectively. Thereafter, the animals received 111In-octreotide intravenously. Animals were killed at 20 h after the injection of the radiopharmaceutical. Organs were dissected, and the amount of radioactivity in the organs and tissues was measured. RESULTS: The administration of 20 mg of Gelofusine in rats or 4 mg in mice was as effective in reducing the renal uptake of 111In-octreotide as the administration of 80 or 20 mg of lysine in rats or mice, respectively, without reducing 111In-octreotide uptake in receptor-positive organs. Plasma expanders based on starch or dextran had no effect on the renal uptake of 111In-octreotide. CONCLUSION: The gelatin-based plasma expander Gelofusine significantly reduced the kidney uptake of 111In-octreotide as effectively as did lysine. Because Gelofusine is a well-known and generally used blood volume substitute that can be applied safely without the induction of toxicity, evaluation of this compound for its potential to reduce the kidney uptake of radiolabeled peptides in patients is warranted.


Subject(s)
Gelatin/administration & dosage , Gelatin/therapeutic use , Kidney/metabolism , Octreotide/analogs & derivatives , Radiation Injuries/prevention & control , Succinates/administration & dosage , Succinates/therapeutic use , Animals , Body Burden , Drug Combinations , Female , Kidney/diagnostic imaging , Kidney/drug effects , Male , Metabolic Clearance Rate , Mice , Mice, Inbred BALB C , Octreotide/adverse effects , Octreotide/pharmacokinetics , Octreotide/therapeutic use , Organ Specificity , Radiation Dosage , Radiation Injuries/etiology , Radiation-Protective Agents/administration & dosage , Radionuclide Imaging , Radiopharmaceuticals/adverse effects , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/therapeutic use , Rats , Rats, Wistar , Species Specificity
6.
J Nucl Med ; 46(9): 1546-51, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16157539

ABSTRACT

UNLABELLED: Studies have demonstrated that the bivalent (111)In-labeled leukotriene B4 (LTB4) antagonist DPC11870 reveals infectious and inflammatory lesions in various rabbit models. The radioactive tracer accumulates quickly at the site of infection and clears rapidly from the circulation, resulting in high-quality images. In this study, 2 new hydrazinonicotinamide (HYNIC)-conjugated compounds that are structurally related to DPC11870 were studied to further improve image quality. METHODS: A bivalent HYNIC-conjugated LTB4 antagonist (MB81) and a monovalent one (MB88) were labeled with (99m)Tc. The radiolabeled compounds were intravenously injected into New Zealand White rabbits with E. coli infection in the left thigh muscle. The imaging characteristics of both compounds were compared with those of the bivalent (111)In-labeled LTB4 antagonist. RESULTS: Both (99m)Tc-labeled LTB4 antagonists revealed the abscess from 2 h after injection onward. Abscess uptake at 8 h after injection was similar for both compounds (0.22 +/- 0.08 percentage injected dose per gram [%ID/g] and 0.36 +/- 0.13%ID/g for the bivalent and monovalent compounds, respectively). However, visualization of the abscess and the quality of the images were better after injection of MB88 than after injection of either of the bivalent LTB4 antagonists. The excellent delineation of the abscess by MB88 was mainly due to the more rapid clearance of this compound from nontarget organs. CONCLUSION: The (99m)Tc-labeled HYNIC conjugated LTB4 antagonists MB88 and MB81 revealed infectious foci in rabbits within a few hours after injection. Imaging characteristics of monovalent (99m)Tc-MB88 were superior to those of the bivalent LTB4 antagonists DPC11870 and MB81. Therefore, of the 3 LTB4 antagonists, the monovalent LTB4 antagonist MB88 is the most potent and promising agent for visualizing and evaluating infection and inflammation in patients.


Subject(s)
Escherichia coli Infections/diagnostic imaging , Escherichia coli Infections/metabolism , Image Enhancement/methods , Leukotriene B4/antagonists & inhibitors , Technetium Compounds/pharmacokinetics , Animals , Escherichia coli Infections/complications , Female , Inflammation/diagnostic imaging , Inflammation/etiology , Inflammation/metabolism , Metabolic Clearance Rate , Organ Specificity , Rabbits , Radionuclide Imaging , Radiopharmaceuticals , Tissue Distribution
7.
J Nucl Med ; 46(5): 786-93, 2005 May.
Article in English | MEDLINE | ID: mdl-15872352

ABSTRACT

UNLABELLED: Radiolabeled leukotriene B4 (LTB4) antagonist DPC11870 is able to reveal infectious and inflammatory foci in distinct animal models. Because previous studies showed that accumulation of (111)In-DPC11870 in the abscess continued although the tracer had cleared from the circulation, we decided to investigate the pharmacodynamics of (111)In-DPC11870 and determine the mechanism of accumulation of the radiolabeled LTB4 antagonist in the abscess. METHODS: (111)In-DPC11870 was intravenously injected in healthy New Zealand White rabbits and rabbits with intramuscular Escherichia coli infection. Pharmacodynamics were studied by serial imaging and by ex vivo counting of dissected tissues. The mechanism of visualization of the abscess was investigated in rabbits with intramuscular infection that was induced 16 h after intravenous administration of (111)In-DPC11870. In addition, heterologous leukocytes and bone marrow cells of a donor rabbit were labeled with (111)In-DPC11870 in vitro and the biodistribution of these in vitro radiolabeled cells was compared with that of (111)In-DPC11870 in rabbits with an infection. RESULTS: The LTB4 antagonist (111)In-DPC11870 revealed the intramuscular abscess in rabbits only a few hours after injection. Quantitative analysis of the images confirmed accumulation of (111)In-DPC11870 in the abscess although the compound had cleared almost completely from the circulation. Radioactivity concentration in the bone marrow decreased more rapidly in infected animals than in healthy animals. Therefore, we hypothesized that (111)In-DPC11870 associates with receptor-positive (bone marrow) cells and accumulated in the abscess because of subsequent migration from the bone marrow to the abscess. Accumulation of radioactivity in the abscess induced 16 h after (111)In-DPC11870 injection was similar to that in animals intravenously injected with the tracer 24 h after induction of the abscess (0.37 +/- 0.16 percentage injected dose [%ID]/g). Moreover, differences in radioactivity concentration in the bone marrow of healthy and infected animals (0.67 +/- 0.29 %ID/g and 0.15 +/- 0.03 %ID/g at 24 h, respectively, after injection) supported our hypothesis. Additional studies with peripheral blood leukocytes and bone marrow cells that were labeled ex vivo with (111)In-DPC11870 showed the ability of these cells to migrate to the abscess (0.40 %ID/g and 0.52 %ID/g for (111)In-DPC11870 bone marrow cells and (111)In-DPC11870 peripheral blood leukocytes, respectively, 24 h after injection). CONCLUSION: The (111)In-labeled LTB4 antagonist DPC11870 accumulates in infectious and inflammatory foci because of binding to LTB4 receptors expressed on activated hematopoietic cells that subsequently migrate to the site of infection, which leads to visualization of the infectious lesions.


Subject(s)
Biphenyl Compounds/pharmacokinetics , Escherichia coli Infections/diagnostic imaging , Escherichia coli Infections/metabolism , Granulocytes/diagnostic imaging , Leukotriene B4/antagonists & inhibitors , Oligopeptides/pharmacokinetics , Pyridines/pharmacokinetics , Tetrazoles/pharmacokinetics , Animals , Female , Metabolic Clearance Rate , Organ Specificity , Rabbits , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution , Whole-Body Counting
8.
Chest ; 126(6): 1954-61, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15596698

ABSTRACT

BACKGROUND: Interleukin (IL)-8 is a chemotactic cytokine that binds with high affinity to receptors on neutrophils. Previously we showed that (99m)Tc-labeled IL-8 is highly suitable for scintigraphic imaging in rabbit models of IM infection and of colitis. STUDY DESIGN: (99m)Tc-labeled IL-8 was tested for its potential to image pulmonary infection in three experimental rabbit models: aspergillosis in immunocompromised rabbits, pneumococcal (Gram-positive) pneumonia, and Escherichia coli-induced (Gram-negative) pneumonia in immunocompetent rabbits (four rabbits in each group). A derivative of hydrazinonicotinamide was used as bifunctional coupling agent to label IL-8 with (99m)Tc. Biodistribution of (99m)Tc IL-8 was determined both by gamma-camera imaging and by counting dissected tissues at 6 h after injection. RESULTS: (99m)Tc IL-8 enabled early (within 2 h after injection) and excellent visualization of localization and extent of pulmonary infection in each of the three experimental models of pulmonary infection. Uptake of (99m)Tc IL-8 in the infected lung and the contralateral lung was (in percentage of the injected dose per gram of tissue +/- SEM) at 6 h after injection 0.63 +/- 0.12 and 0.12 +/- 0.02 (aspergillosis), 0.89 +/- 0.04 and 0.44 +/- 0.04 (pneumococcal pneumonia), and 1.53 +/- 0.12 and 0.36 +/- 0.06 (E coli pneumonia), respectively. In the E coli model, uptake of (99m)Tc IL-8 in the focus of infection even exceeded uptake in the kidneys, the main clearing organs. CONCLUSION: (99m)Tc IL-8 offers many advantages over the conventionally used radiopharmaceuticals to image pulmonary infection, (67)Ga citrate and radiolabeled leukocytes, ie, rapid and easy preparation, short time span between injection and imaging, low radiation burden and, most importantly, clear delineation of the infectious foci.


Subject(s)
Aspergillosis/diagnostic imaging , Interleukin-8 , Lung Diseases, Fungal/diagnostic imaging , Organotechnetium Compounds , Pneumonia, Bacterial/diagnostic imaging , Radiopharmaceuticals , Animals , Aspergillosis/immunology , Escherichia coli Infections/diagnostic imaging , Immunocompromised Host , Lung/diagnostic imaging , Lung Diseases, Fungal/immunology , Pneumonia, Pneumococcal/diagnostic imaging , Rabbits , Radionuclide Imaging
9.
J Nucl Med ; 45(10): 1747-53, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15471844

ABSTRACT

UNLABELLED: Radiolabeled chemotactic peptides have been studied for their applicability to the visualization of infectious and inflammatory foci. Because a radiolabeled leukotriene B4 (LTB4) antagonist allowed visualization of intramuscular E. coli abscesses in rabbits within a few hours after injection, we decided to test the imaging characteristics of this agent in a more clinically relevant model of pulmonary aspergillosis. The pharmacokinetics and imaging characteristics of the 111In-labeled LTB4 antagonist DPC11870 were studied in New Zealand White rabbits with experimental pulmonary aspergillosis infection. The imaging characteristics of 111In-DPC11870 were compared with those of 67Ga-citrate, a radiopharmaceutical commonly used to detect pulmonary infections in patients. METHODS: Pulmonary aspergillosis was induced in the left lung of rabbits by intratracheal inoculation of 1 x 10(8) conidia of Aspergillus fumigatus. Three days after the inoculation, the rabbits received 111In-DPC11870 or 67Ga-citrate intravenously. Images were acquired at several time points up to 24 h after injection. RESULTS: Pulmonary aspergillosis was visualized with both agents. Images acquired after injection of 111In-DPC11870 showed uptake in the pulmonary lesions from 6 h after injection. Because of accumulation at the site of infection and clearance from the background, the images improved with time. Region-of-interest analysis at 24 h after injection revealed infected lung-to-normal lung ratios of 5.0 +/- 1.5 for 111In-DPC11870 and 2.9 +/- 0.6 for 67Ga-citrate. CONCLUSION: The radiolabeled LTB4 antagonist DPC11870 clearly delineated experimentally induced pulmonary aspergillosis in rabbits. Images acquired at 24 h after injection of 111In-DPC11870 were superior to those obtained after injection of 67Ga-citrate.


Subject(s)
Aspergillosis/diagnostic imaging , Aspergillosis/metabolism , Biphenyl Compounds/pharmacokinetics , Leukotriene B4/antagonists & inhibitors , Lung Diseases, Fungal/diagnostic imaging , Lung Diseases, Fungal/metabolism , Oligopeptides/pharmacokinetics , Pyridines/pharmacokinetics , Tetrazoles/pharmacokinetics , Animals , Citrates/pharmacokinetics , Female , Gallium/pharmacokinetics , Indium Radioisotopes/pharmacokinetics , Leukotriene B4/metabolism , Metabolic Clearance Rate , Organ Specificity , Rabbits , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Tissue Distribution
10.
J Nucl Med ; 45(2): 327-37, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14960657

ABSTRACT

UNLABELLED: Radioimmunotherapy (RIT) can be performed with various radionuclides. We tested the stability, biodistribution, and therapeutic efficacy of various radioimmunoconjugates ((131)I, (88/90)Y, (177)Lu, and (186)Re) of chimeric antirenal cell cancer monoclonal antibody G250 (mAb cG250) in nude mice with subcutaneous renal cell cancer (RCC) tumors. METHODS: The (88/90)Y and (177)Lu labeling procedures of cG250 conjugated with cyclic diethylenetriaminepentaacetic acid anhydride (cDTPA), isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), or 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) were characterized. Stability of the labeled conjugates in plasma at 37 degrees C was assessed. Biodistribution and therapeutic efficacy of labeled cG250 were compared in nude mice with SK-RC-52 human RCC xenografts. RESULTS: Both SCN-Bz-DTPA and DOTA were stable in vitro (<5% release of the radiolabel during 14 and 21 d of incubation) and in vivo (uptake in bone

Subject(s)
Carcinoma, Renal Cell/radiotherapy , Kidney Neoplasms/radiotherapy , Pentetic Acid/analogs & derivatives , Radioimmunotherapy , Animals , Antibodies, Monoclonal , Humans , Iodine Radioisotopes/therapeutic use , Isotope Labeling , Lutetium , Mice , Mice, Nude , Radioisotopes/therapeutic use , Rhenium , Tissue Distribution , Yttrium Radioisotopes/therapeutic use
11.
J Nucl Med ; 45(1): 89-93, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14734679

ABSTRACT

UNLABELLED: The use of radiolabeled leukocytes is considered the gold standard for scintigraphic imaging of inflammatory bowel disease. The disadvantages of (99m)Tc-hexamethylpropyleneamine oxime (HMPAO)-leukocytes, however, encourage the search for new imaging agents with at least similar diagnostic accuracy but without the laborious preparation and subsequent risk of contamination. In this study we investigated the imaging characteristics of a new imaging agent that specifically binds to the leukotriene B(4) (LTB(4)) receptors expressed on neutrophils. Imaging characteristics of the (111)In-labeled LTB(4) antagonist (DPC11870) were compared with those of (18)F-FDG and (99m)Tc-HMPAO-granulocytes in a rabbit model of experimental colitis. METHODS: Acute colitis was induced in New Zealand White (NZW) rabbits by infusion of trinitrobenzene sulfonic acid in the descending colon. Forty-eight hours after induction of colitis, all animals were injected intravenously with (99m)Tc-granulocytes, (18)F-FDG, or (111)In-DPC11870. The pharmacokinetics and biodistribution were studied by serial scintigraphic imaging and by ex vivo counting of dissected tissues. RESULTS: All 3 radiopharmaceuticals showed the inflamed colon as early as 1 h after injection. However, compared with (99m)Tc-granulocytes, both (111)In-DPC11870 and (18)F-FDG were superior in revealing the inflamed lesions. The biodistribution data showed that uptake of (111)In-DPC11870 in the inflamed colon was highest (0.72 +/- 0.18 percentage injected dose per gram [%ID/g]), followed by uptake of (99m)Tc-granulocytes (0.40 +/- 0.11 %ID/g) and of (18)F-FDG (0.16 +/- 0.04 %ID/g). Because of low activity concentrations in the noninflamed colon, the radiolabeled LTB(4) antagonist also revealed the highest ratio of affected colon to unaffected colon (11.6 for (111)In-DPC11870, 5.5 for (99m)Tc-granulocytes, and 4.1 for (18)F-FDG). CONCLUSION: The radiolabeled LTB(4) antagonist DPC11870 clearly delineated acute colitis lesions in NZW rabbits within 1 h after injection. Because of high uptake in the inflamed lesions and a low activity concentration in the noninflamed colon, images acquired with (111)In-DPC11870 were better than those acquired with (99m)Tc-granulocytes or (18)F-FDG.


Subject(s)
Biphenyl Compounds/pharmacokinetics , Colitis/diagnostic imaging , Colitis/metabolism , Leukotriene B4/antagonists & inhibitors , Leukotriene B4/metabolism , Neutrophils/diagnostic imaging , Neutrophils/metabolism , Oligopeptides/pharmacokinetics , Pyridines/pharmacokinetics , Tetrazoles/pharmacokinetics , Animals , Colitis/chemically induced , Female , Fluorodeoxyglucose F18/pharmacokinetics , Granulocytes/diagnostic imaging , Granulocytes/metabolism , Isotope Labeling/methods , Organ Specificity , Rabbits , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Reproducibility of Results , Sensitivity and Specificity , Technetium Tc 99m Exametazime/pharmacokinetics , Tissue Distribution , Whole-Body Counting
12.
Cancer Biother Radiopharm ; 18(4): 655-61, 2003 Aug.
Article in English | MEDLINE | ID: mdl-14503961

ABSTRACT

Antibody-PET imaging might be of value for the selection of radioimmunotherapy (RIT) candidates to confirm tumor targeting and to estimate radiation doses to tumor and normal tissues. One of the requirements to be set for such a scouting procedure is that the biodistributions of the diagnostic and therapeutic radioimmunoconjugates should be similar. In the present study we evaluated the potential of the positron emitters zirconium-89 ((89)Zr) and iodine-124 ((124)I) for this approach, as these radionuclides have a relatively long half-life that matches with the kinetics of MAbs in vivo (t(1/2) 3.27 and 4.18 days, respectively). After radiolabeling of the head and neck squamous cell carcinoma (HNSCC)-selective chimeric antibody (cMAb) U36, the biodistribution of two diagnostic (cMAb U36-N-sucDf-(89)Zr and cMAb U36-(124)I) and three therapeutic radioimmunoconjugates (cMAb U36-p-SCN-Bz-DOTA-(88)Y-with (88)Y being substitute for (90)Y, cMAb U36-(131)I, and cMAb U36-MAG3-(186)Re) was assessed in mice with HNSCC-xenografts, at 24, 48, and 72 hours after injection. Two patterns of biodistribution were observed, one pattern matching for (89)Zr- and (88)Y-labeled cMAb U36 and one pattern matching for (124)I-, (131)I-, and (186)Re-cMAb U36. The most remarkable differences between both patterns were observed for uptake in tumor and liver. Tumor uptake levels were 23.2 +/- 0.5 and 24.1 +/- 0.7%ID/g for the (89)Zr- and (88)Y-cMAb U36 and 16.0 +/- 0.8, 15.7 +/- 0.79 and 17.1 +/- 1.6%ID/g for (124)I-, (131)I-, and (186)Re-cMAb U36-conjugates, respectively, at 72 hours after injection. For liver these values were 6.9 +/- 0.8 ((89)Zr), 6.2 +/- 0.8 ((88)Y), 1.7 +/- 0.1 ((124)I), 1.6 +/- 0.1 ((131)I), and 2.3 +/- 0.1 ((186)Re), respectively. These preliminary data justify the further development of antibody-PET with (89)Zr-labeled MAbs for scouting of therapeutic doses of (90)Y-labeled MAbs. In such approach (124)I-labeled MAbs are most suitable for scouting of (131)I- and (186)Re-labeled MAbs.


Subject(s)
Immunoconjugates/pharmacokinetics , Iodine Radioisotopes , Radioisotopes , Zirconium , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacokinetics , Carcinoma, Squamous Cell/diagnostic imaging , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/radiotherapy , Cell Line, Tumor , Female , Glycoproteins/immunology , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/radiotherapy , Humans , Hyaluronan Receptors/immunology , Immunoconjugates/chemistry , Isotope Labeling , Mice , Mice, Nude , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/immunology , Recombinant Fusion Proteins/pharmacokinetics , Rhenium , Time Factors , Tissue Distribution , Tomography, Emission-Computed , Xenograft Model Antitumor Assays , Yttrium Radioisotopes
13.
J Nucl Med ; 44(7): 1087-91, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12843226

ABSTRACT

UNLABELLED: Several radiolabeled chemotactic peptides have been tested for their suitability to show infection and inflammation. Leukotriene B(4) (LTB(4)) receptor-binding ligands could be useful agents for revealing neutrophilic infiltrations because the LTB(4) receptor is abundantly expressed on neutrophils after an inflammatory stimulus. In this study, we investigated the in vivo and in vitro characteristics of a new hydrophilic (111)In-labeled LTB(4) antagonist. METHODS: The LTB(4) antagonist DPC11870-11 was labeled with (111)In and intravenously injected into New Zealand White rabbits with Escherichia coli infection in the left thigh muscle. The pharmacokinetics and biodistribution were studied by serial scintigraphic imaging (0-24 h after injection) and by ex vivo counting of dissected tissues (6 and 24 h after injection). The receptor-mediated in vivo localization of the compound was investigated in 3 rabbits that received an excess of nonradioactive indium-labeled agent 2 min before the administration of the (111)In-labeled LTB(4) antagonist. RESULTS: In rabbits with intramuscular E. coli infection, the abscess was visualized as early as 2 h after injection. Accumulation in the abscess increased with time, resulting in excellent images at 6 h after injection. Blood clearance was rapid in the first hours after injection (alpha-half-life = 30 +/- 6 min, 85%; beta-half-life = 25.7 +/- 0.8 h, 15%). Abscess-to-background ratios, as derived from the region-of-interest analysis, increased to 34 +/- 7 at 24 h after injection. The images of both groups showed moderate uptake in the liver, spleen, kidneys, and bone marrow. No activity was seen in the bladder, indicating almost complete retention in the kidneys. The uptake in the abscess could be blocked completely by injection of an excess of nonradioactive agent, indicating a specific receptor-ligand interaction of the radiolabeled agent in the infected tissue. Biodistribution data showed that after saturation of the LTB(4) receptor, the abscess uptake, in percentage injected dose per gram, was significantly reduced (0.03 +/- 0.02 vs. 0.24 +/- 0.06, P = 0.008). CONCLUSION: The modified LTB(4) antagonist showed infectious foci rapidly after injection because of specific receptor-ligand interaction. Because of the high abscess-to-background ratios that were obtained and the fact that no accumulation of radioactivity was observed in the gastrointestinal tract, this compound has excellent characteristics for revealing infectious and inflammatory foci.


Subject(s)
Biphenyl Compounds/pharmacokinetics , Escherichia coli Infections/diagnostic imaging , Escherichia coli Infections/metabolism , Isotope Labeling/methods , Oligopeptides/pharmacokinetics , Pyridines/pharmacokinetics , Tetrazoles/pharmacokinetics , Animals , Biphenyl Compounds/blood , Biphenyl Compounds/chemical synthesis , Indium Radioisotopes/blood , Indium Radioisotopes/pharmacokinetics , Myositis/diagnostic imaging , Myositis/metabolism , Oligopeptides/blood , Oligopeptides/chemical synthesis , Organ Specificity , Pyridines/blood , Pyridines/chemical synthesis , Rabbits , Radionuclide Imaging , Radiopharmaceuticals/blood , Radiopharmaceuticals/pharmacokinetics , Receptors, Leukotriene B4/antagonists & inhibitors , Receptors, Leukotriene B4/metabolism , Tetrazoles/blood , Tetrazoles/chemical synthesis , Thigh/diagnostic imaging , Tissue Distribution
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