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At least 19 recordsLinked to original sources
PubMed2005

A comparison of PET imaging characteristics of various copper radioisotopes.

PURPOSE: PET radiotracers which incorporate longer-lived radionuclides enable biological processes to be studied over many hours, at centres remote from a cyclotron. This paper examines the radioisotope characteristics, imaging performance, radiation dosimetry and production modes of the four copper radioisotopes, ( 60)Cu,( 61)Cu,( 62)Cu and( 64)Cu, to assess their merits for different PET imaging applications. METHODS: Spatial resolution, sensitivity, scatter fraction and noise-equivalent count rate (NEC) are predicted for( 60)Cu,( 61)Cu,( 62)Cu and( 64)Cu using a model incorporating radionuclide decay properties and scanner parameters for the GE Advance scanner. Dosimetry for( 60)Cu,( 61)Cu and( 64)Cu is performed using the MIRD model and published biodistribution data for copper(II) pyruvaldehyde bis(N(4)-methyl)thiosemicarbazone (Cu-PTSM). RESULTS: (60)Cu and( 62)Cu are characterised by shorter half-lives and higher sensitivity and NEC, making them more suitable for studying the faster kinetics of small molecules, such as Cu-PTSM.( 61)Cu and( 64)Cu have longer half-lives, enabling studies of the slower kinetics of cells and peptides and prolonged imaging to compensate for lower sensitivity, together with better spatial resolution, which partially compensates for loss of image contrast.( 61)Cu-PTSM and( 64)Cu-PTSM are associated with radiation doses similar to [(18)F]-fluorodeoxyglucose, whilst the doses for( 60)Cu-PTSM and( 62)Cu-PTSM are lower and more comparable with H(2) (15)O. CONCLUSION: The physical and radiochemical characteristics of the four copper isotopes make each more suited to some imaging tasks than others. The results presented here assist in selecting the preferred radioisotope for a given imaging application, and illustrate a strategy which can be extended to the majority of novel PET tracers.

Computer Simulation↗
PubMed1992

Copper metabolism in new mutant Long-Evans cinnamon (LEC) rats causing hereditary hepatitis: gastrointestinal absorption and distribution of radioisotopic copper (64Cu).

Long-Evans cinnamon (LEC) rats 60 days old showed a concentration of 127.7 +/- 10.9 micrograms/g of Cu in the liver, compared to 1.6 +/- 0.1 micrograms/g in Fischer rats 60 days old. At 2 hr after an oral injection of 64Cu, total retention of 64Cu in the whole blood, liver and kidneys was 16.8 +/- 3.4% of the dose in LEC rats, compared to 13.1 +/- 1.3% in Fischer rats. The recovery rates of retained-64Cu in the livers in LEC and Fischer rats were 82% and 59%, respectively. More than 90% and about 60% of hepatic 64Cu existed in the cytosol fraction in LEC and Fischer rats, respectively. Furthermore, more than 90% of the cytosolic 64Cu was found as MT in LEC rats. In Fischer rats, this proportion was about 60%. In the duodenum mucosal cytosol fraction from LEC rats, about 50% of 64Cu was bound to metallothionein (MT) protein. In Fischer rats, this proportion was less than 20%. When a 64Cu compound was intraperitoneally injected, 70% and only 15% were recovered in the liver 20 hr after the injection in LEC and Fischer rats, respectively. Furthermore, LEC rats showed very low 64Cu activity in the serum, and their duodenal activities were slightly low compared to Fischer rats. These results suggest that the gross accumulation of hepatic Cu is mainly due to deficient excretion of Cu from the liver.

Animals↗
PubMedDate not supplied

Comparison of four bifunctional chelates for radiolabeling monoclonal antibodies with copper radioisotopes: biodistribution and metabolism.

The bifunctional chelating agents (BFCs), 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-1,4 ,8, 11-tetraacetic acid (BAT), 6-[p-(isothiocyanato)benzyl]-1,4,8, 11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (SCN-TETA), 4-[(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]benzoic acid (CPTA), and 1-[(1,4, 7,10,13-pentaazacyclopentadec-1-yl)methyl]benzoic acid (PCBA), were synthesized and conjugated to the anti-colorectal monoclonal antibody (mAB), 1A3, and antibody fragments, 1A3-F(ab')2, for radiolabeling with 64,67CU and comparison in animal models. In vivo metabolism studies were carried out in liver and kidneys in order to correlate the nature of the metabolites formed to the uptake and retention of the radiolabel in each organ. Animal biodistribution studies were performed in Golden Syrian hamsters bearing the GW39 human colon cancer tumors and in normal Sprague-Dawley rats. All conjugates showed good tumor uptake in hamsters. Biodistribution in rats showed that 64CU-BAT-2IT-1A3 had the lowest liver and kidney uptake of the intact 1A3 conjugates (p < 0.03), whereas in hamsters, there were no significant differences in liver and kidney uptake between the four intact BFC-1A3 conjugates. Tumor-bearing hamsters injected with 64CU-CPTA-1A3-F(ab')2 and 64CU-PCBA-1A3-F(ab')2 had from 3 to 7 times greater uptake in the kidneys than hamsters given 64CU-labeled BAT and SCN-TETA 1A3-F(ab')2 conjugates, while rats injected with 64Cu-CPTA-1A3-F(ab')2 and 64Cu-PCBA-1A3-F(ab')2 had nearly twice the uptake. The in vivo metabolism of the mAbs 1A3 and 1A3-F(ab')2 radiolabeled with 67Cu through the SCN-TETA, CPTA, and PCBA BFCs was investigated by excising the livers and kidneys of normal rats from 1-5 days post-injection of the radiolabeled conjugates. Liver and kidney homogenates were analyzed by size exclusion chromatography and thin layer chromatography (TLC). The size exclusion chromatography data showed that all of the 67Cu-labeled 1A3-F(ab')2 conjugates were > 85% degraded in the kidneys to small molecular weight metabolites by 1 day post-injection. In contrast, in the liver at 1 day post-injection, greater than 70% of the 67Cu-labeled 1A3 conjugates were unmetabolized. By day 5, a 35 kDa peak appeared in the liver of rats injected with the 67 Cu-labeled 1A3 conjugates, possibly due to transchelation of the 67Cu to proteins. Superoxide dismutase chromatographically elutes at the same retention time as this 67Cu-labeled metabolite. The TLC data indicate that the low molecular weight metabolite (< 5 kDa) of both 67Cu-CPTA-1A3 and 67Cu-CPTA-1A3-F(ab')2 conjugates co-chromatographed with a 67Cu-CPTA-epsilon-lysine standard. Our data suggest that chelate charge and lipophilicity play a large role in kidney retention of 64/67Cu-labeled BFC-1A3-F(ab')2 conjugates, while transchelation of the copper label appears to be the major factor for liver accumulation of 64/67Cu-labeled BFC-1A3 conjugates.

Animals↗
PubMed2006

A simple and selective method for the separation of Cu radioisotopes from nickel.

Separation of copper radioisotopes from a nickel target is normally performed using solvent extraction or anion exchange rather than using cationic exchange. A commonly held opinion is that cationic exchangers have very similar thermodynamic complexation constants for metallic ions with identical charges, therefore making the separation very difficult or impossible. The results presented in this article indicate that the selectivity of Chelex-100 (a cationic ion exchanger) for Cu radioisotope and Ni ions not only depends on the thermodynamic complexation constant in the resin but also markedly varies with the concentration of mobile H+. In our developed method, separation of copper radioisotopes from a nickel target was fulfilled in a column filled with Chelex-100 via controlling the HNO3 concentration of the eluent, and the separation is much more effective, simple and economical in comparison with the common method of anion exchange. For an irradiated nickel target with 650 mg Ni, after separation, the loss of Cu radioisotopes in the nickel portion was reduced from 30% to 0.33% of the total initial radioactivity and the nickel mixed into the radioactive products was reduced from 9.5 to 0.5 mg. This significant improvement will make subsequent labeling much easier and reduce consumption of chelating agents and other chemicals during labeling. If the labeled agent is used in human medical applications, the developed method will significantly decrease the uptake of Ni and chelating agents by patients, therefore reducing both the stress on human body associated with clearing the chemicals from blood and tissue and the risk of various types of acute and chronic disorder due to exposure to Ni.

Chromatography, Ion Exchange↗
PubMed1989

Similar lethal effect in mammalian cells for two radioisotopes of copper with different decay schemes, 64Cu and 67Cu.

The decays of 64Cu incorporated in human malignant (A549) or monkey nonmalignant (CVI) cells lead to cell death. When plotted as a function of the radioactivity introduced in the growth medium (microCi/ml at t = 0), the residual colony-forming capability decreases exponentially. The slope of the corresponding curve is steeper for A549 than for CV1 cells. Different data show that the cellular lethal event is a consequence of 64Cu transmutation and not of the irradiation by the simultaneously emitted beta- and beta+ particles. Liquid holding results show that the lethal event is irreparable. The decays of 67Cu, another radioisotope of copper, lead to cell death with the same exponential survival curve and the same lethal efficiency as for 64Cu, in spite of their different decay schemes. The lethal efficiency of both copper isotopes is close to that of 125I utilized in the form of iododeoxyuridine under the same experimental conditions as 64Cu and 67Cu. The high lethal efficiency of radioactive copper transmutations raises questions about the role in DNA functioning of copper atoms known to be present in trace amounts in this macromolecule. The lethal consequence of radioactive copper transmutations suggests that the copper atoms bound to DNA are essential for cellular functioning.

Animals↗
PubMed1998

The in vivo behavior of copper-64-labeled azamacrocyclic complexes.

The use of copper radioisotopes in imaging and therapy applications has created a greater need for bifunctional chelates (BFCs) for complexing copper radioisotopes to biomolecules. It has been demonstrated that the charge and lipophilicity of the Cu-BFC complex has a significant effect on the in vivo behavior of the radiolabeled Cu-BFC-biomolecule conjugate. To evaluate the effects of charge, stability, and macrocyclic backbone size on the biological behavior of 64Cu complexes, a series of macrocyclic 64Cu complexes have been prepared, and the biodistributions of these agents were evaluated in normal Sprague-Dawley rats. Two macrocyclic backbones, dodecane and tetradecane, were evaluated; cyclen, DOTA, and DO2A were dodecane backbone derivatives, and cyclam, TETA, and et-cyclam were tetradecane backbone derivatives. The biodistributions of the 64Cu-labeled complexes correlated with differences in the size of the macrocycle backbone and the formal charge of the complex. All compounds showed uptake and clearance through the liver and kidneys; however, the positively charged 64Cu complexes showed significantly higher uptake in both of these organs than did the negatively charged or neutral complexes. 64Cu-TETA, a negatively charged complex with the tetradecane backbone, had the most efficient clearance by 24 hours' postinjection. These data suggest that negatively charged complexes may have more favorable clearance properties when used as BFCs.

Animals↗
PubMed1998

Synthesis and evaluation of a monocationic copper(II) radiopharmaceutical derived from N-(2-pyridylmethyl)-N'-(salicylaldimino)-1,3-propanediamine.

The monocationic 67Cu complex of N-(2-pyridylmethyl)-N'-(salicylaldimino)-1,3-propanediamine was obtained in high radiochemical purity by reaction of 67Cu2+ with the ligand in ethanol solution. Although this compound exhibited low heart uptake, the desired myocardial retention was observed over the 30 min time period studied in a rat model. Since the octanol/water partition coefficient of [67Cu]Cu(II)-N-(2-pyridylmethyl)-N'-(salicylaldiminato)-1,3- propanediamine] is lower than a value believed to be the optimal myocardial uptake, it is likely that derivatives of this compound with a higher lipophilicity merit further investigation for use in myocardial imaging with copper radioisotopes.

Animals↗
PubMed2004

Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes.

The increased use of copper radioisotopes in radiopharmaceutical applications has created a need for bifunctional chelators (BFCs) that form stable radiocopper complexes and allow covalent attachment to biological molecules. The chelators most commonly utilized for labeling copper radionuclides to biomolecules are analogues of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA); however, recent reports have communicated the instability of the radio-Cu(II)-TETA complexes in vivo. A class of bicyclic tetraazamacrocycles, the ethylene "cross-bridged" cyclam (CB-cyclam) derivatives, form highly kinetically stable complexes with Cu(II) and therefore may be less susceptible to transchelation than their nonbridged analogues in vivo. Herein we report results on the relative biological stabilities and identification of the resulting radiolabeled metabolites of a series of (64)Cu-labeled macrocyclic complexes. Metabolism studies in normal rat liver have revealed that the (64)Cu complex of 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane ((64)Cu-CB-TE2A) resulted in significantly lower values of protein-associated (64)Cu than (64)Cu-TETA [13 +/- 6% vs 75 +/- 9% at 4 h]. A similar trend was observed for the corresponding cyclen derivatives, with the (64)Cu complex of 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane ((64)Cu-CB-DO2A) undergoing less transchelation than the (64)Cu complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid ((64)Cu-DOTA) [61 +/- 14% vs 90.3 +/- 0.5% protein associated (64)Cu at 4 h]. These data indicate that the structurally reinforcing cross-bridge enhances in vivo stability by reducing metal loss to protein in both the cyclam and cyclen cross-bridged (64)Cu complexes and that (64)Cu-CB-TE2A is superior to (64)Cu-CB-DO2A in that regard. These findings further suggest that a bifunctional chelator derivative of CB-TE2A is a highly desirable alternative for labeling copper radionuclides to biological molecules for diagnostic imaging and targeted radiotherapy.

Animals↗
PubMed1989

Kinetics of copper-PTSM in isolated hearts: a novel tracer for measuring blood flow with positron emission tomography.

Copper(II) pyruvaldehyde bis(N4-methylthiosemicarbazone) ([Cu]PTSM) has shown potential as a flow tracer and can be labeled with the generator-produced positron emitting radionuclide 62Cu as well as with other copper radioisotopes. To define the myocardial handling of [Cu]PTSM, the externally detected single pass extraction and retention of [67Cu]PTSM was characterized after bolus administration in 12 isolated rabbit hearts perfused with erythrocyte-enriched modified Krebs-Henseleit buffer which permitted physiologic flow rates. The myocardial residual (extraction) fraction at control flow rates (approximately 1.5 ml/g/min) was 45 +/- 7(s.d.)% (n = 12), and was invariate with ischemia (flow = 0.15 ml/g/min, n = 4), hyperemia (flow = 3 ml/g/min, n = 4) or with hypoxia induced by perfusion at control flow rates with hypoxic buffer (n = 4) (residual fraction 45 +/- 20, 43 +/- 8, and 49 +/- 8%, respectively, p = N.S.). Once extracted, the tracer was retained with a biologic t1/2 of greater than 3600 min in all groups. The high single-pass extraction, which is not influenced by flow, and the prolonged retention of this tracer under diverse conditions indicate that [Cu]PTSM could be a useful tracer for measuring blood flow with positron emission tomography.

Animals↗
PubMed1987

Abnormalities of copper in Gilles de la Tourette syndrome.

The Gilles de la Tourette syndrome is a disorder whose etiology and pathogenesis are little understood. The number of biochemical abnormalities described in this disorder is minimal. Ten of a total of 80 patients were found to have an abnormally low serum copper. A report is presented on two patients who consented to further detailed investigation and in whom copper radioisotope studies were carried out. Both exhibited abnormalities of copper handling, in that we observed an abnormally fast disappearance of copper from the plasma and an abnormally slow uptake by the liver. The rates of intestinal absorption and urinary excretion were normal. We did not identify an abnormal site of sequestration of the metal in the body.

Adult↗
PubMed2006

Investigation of copper-azamacrocyclic complexes by high-performance liquid chromatography.

The use of copper radioisotopes in imaging and therapy has prompted an increased interest in chelators which form stable copper complexes, such as Cu(II)-azamacrocyclic complexes. The effects of charge, stability and the size of the macrocyclic backbone of the Cu(II)-azamacrocyclic complexes on biological behavior have been evaluated. Here we report a reversed-phase high-performance liquid chromatography (HPLC) method to separate several Cu(II)-azamacrocyclic complexes, including Cu(II) complexes of 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A) and 4,10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane (CB-DO2A). Absorbance at 280 nm was used to monitor the complexes as they eluted from the reversed-phase column. The effects of the concentration of the buffer, the pH of the buffered mobile phase and the concentration of the organic modifier, methanol, on the separation were investigated. Separation of these copper complexes by ion-pair HPLC with the use of a mass spectrometry-compatible ion-pair reagent, triethylammonium acetate, in the mobile phase at pH 6.3 is also presented. The reversed-phase chromatographic conditions utilized also allow the pK(a)s of Cu-TETA and the log(k'w) values of Cu-CB-TE2A, Cu-TETA and Cu-CB-DO2A to be estimated.

Aza Compounds↗
PubMed1994

Effects of ischemia-reperfusion injury on myocardial single pass extraction and retention of Cu-PTSM in perfused rat hearts: comparison with 201T1 and 14C-iodoantipyrine.

The effects of ischemia-reperfusion-induced myocardial damage on the single pass extraction and retention of 64Cu-pyruvaldehyde-di(N4-methylthiosemicabazone) (64Cu-PTSM) in perfused rat hearts were compared to these effects on that of 201T1 and 14C-iodoantipyrine. 201T1 and 14C-iodoantipyrine did not show significant changes, but in the case of 64Cu-PTSM, the single pass extraction and retention was reduced with reperfusion. These findings indicate that ischemia-reperfusion-induced myocardial damage decrease the generator-produced 62Cu-labeled 62Cu-PTSM extraction and retention, and that 62Cu-PTSM might have potential not only as a blood flow tracer but also as a functional tracer.

Animals↗
PubMed2002

Correction of the copper transport defect of Menkes patient fibroblasts by expression of two forms of the sheep Wilson ATPase.

The Wilson disease (WD) protein (ATP7B) is a copper-transporting P-type ATPase that is responsible for the efflux of hepatic copper into the bile, a process that is essential for copper homeostasis in mammals. Compared with other mammals, sheep have a variant copper phenotype and do not efficiently excrete copper via the bile, often resulting in excessive copper accumulation in the liver. To investigate the function of sheep ATP7B and its potential role in the copper-accumulation phenotype, cDNAs encoding the two forms of ovine ATP7B were transfected into immortalised fibroblast cell lines derived from a Menkes disease patient and a normal control. Both forms of ATP7B were able to correct the copper-retention phenotype of the Menkes cell line, demonstrating each to be functional copper-transporting molecules and suggesting that the accumulation of copper in the sheep liver is not due to a defect in the copper transport function of either form of sATP7B.

Adenosine Triphosphatases↗
PubMed2002

Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals.

Cisplatin is a chemotherapeutic drug used to treat a variety of cancers. Both intrinsic and acquired resistance to cisplatin, as well as toxicity, limit its effectiveness. Molecular mechanisms that underlie cisplatin resistance are poorly understood. Here we demonstrate that deletion of the yeast CTR1 gene, which encodes a high-affinity copper transporter, results in increased cisplatin resistance and reduced intracellular accumulation of cisplatin. Copper, which causes degradation and internalization of Ctr1 protein (Ctr1p), enhances survival of wild-type yeast cells exposed to cisplatin and reduces cellular accumulation of the drug. Cisplatin also causes degradation and delocalization of Ctr1p and interferes with copper uptake in wild-type yeast cells. Mouse cell lines lacking one or both mouse Ctr1 (mCtr1) alleles exhibit increased cisplatin resistance and decreased cisplatin accumulation in parallel with mCtr1 gene dosage. We propose that cisplatin uptake is mediated by the copper transporter Ctr1p in yeast and mammals. The link between Ctr1p and cisplatin transport may explain some cases of cisplatin resistance in humans and suggests ways of modulating sensitivity and toxicity to this important anticancer drug.

Animals↗
PubMed2006

Mammary gland copper transport is stimulated by prolactin through alterations in Ctr1 and Atp7A localization.

Milk copper (Cu) concentration declines and directly reflects the stage of lactation. Three Cu-specific transporters (Ctr1, Atp7A, Atp7B) have been identified in the mammary gland; however, the integrated role they play in milk Cu secretion is not understood. Whereas the regulation of milk composition by the lactogenic hormone prolactin (PRL) has been documented, the specific contribution of PRL to this process is largely unknown. Using the lactating rat as a model, we determined that the normal decline in milk Cu concentration parallels declining Cu availability to the mammary gland and is associated with decreased Atp7B protein levels. Mammary gland Cu transport was highest during early lactation and was stimulated by suckling and hyperprolactinemia, which was associated with Ctr1 and Atp7A localization at the plasma membrane. Using cultured mammary epithelial cells (HC11), we demonstrated that Ctr1 stains in association with intracellular vesicles that partially colocalize with transferrin receptor (recycling endosome marker). Atp7A was primarily colocalized with mannose 6-phosphate receptor (M6PR; late endosome marker), whereas Atp7B was partially colocalized with protein disulfide isomerase (endoplasmic reticulum marker), TGN38 (trans-Golgi network marker) and M6PR. Prolactin stimulated Cu transport as a result of increased Ctr1 and Atp7A abundance at the plasma membrane. Although the molecular mechanisms responsible for these posttranslational changes are not understood, transient changes in prolactin signaling play a role in the regulation of mammary gland Cu secretion during lactation.

Adenosine Triphosphatases↗
PubMed2004

Pharmacokinetic distribution of 67Cu(II)2[3,5-diisopropyl(carboxy-14C)salicylate]4 among murine tissues.

Non-toxic doses of tetrakis-mu-3,5-diisopropylsalicylatodicopper(II) [Cu(II)2(3,5-DIPS)4] have been found to have anti-inflammatory, analgesic, anti-ulcer, anti-colitis, anti-convulsant, anti-cancer, anti-mutagenic, anti-carcinogenic, and anti-diabetic activities and, in addition, facilitates recovery from lethal irradiation and ischemia-reperfusion injuries. The goal of this research was to determine the time-dependent tissue distribution and persistence of 67Cu and the 14C labeled salicylate ligand, carboxy-14C-3, 5-diisopropylsalicylate [3,5-DIP(carboxy-14C)S], following subcutaneous administration of a 50 micromole per kilogram of body mass dose of double labeled tetrakis-mu-3,5-diisopropyl[carboxy-14C]salicylatodiaquo [67Cu]dicopper(II) 67Cu(II)4[3,5-DIP(carboxy-14C)S]4. This compound was administered to nine groups of six 20 gram female C57BL/6 mice and blood, liver, kidney, intestine, lung, thymus, femur, muscle, spleen, and brain tissues removed and analyzed for 67Cu and 14C at 0.5, 1, 3, 6, 12, 24, 48, 72, and 96 hours after treatment. These data were then analyzed using a pharmacokinetic model simulation program. Both 67Cu and 14C were found in all tissues as well as urine and feces at 0.5 hour after administration. As anticipated, 67Cu entered the liver storage pool; it was conserved by the kidneys, and subsequently underwent release in maintaining 67Cu levels in all other tissues. While the presence of 67Cu correlated with the presence of the salicylate ligand, 3,5-DIP (carboxy-14C)S, early in the course of this experiment, the ligand was lost via ligand exchange and could not be measured in blood, kidney, intestine, lung, thymus, spleen, and brain after 24 hours following administration. However, 3,5-DIP(carboxy-14C)S persisted in liver, femur, and muscle throughout the 5-day period of study. It is suggested that marked lipophilicity accounts for its very rapid distribution to all tissues wherein it undergoes ligand exchange as 67Cu is incorporated into Cu-dependent enzymes and proteins and persists in tissues based upon physiological demand for Cu in meeting normal biochemical requirements.

Animals↗