Molecular recognition and metal ion template synthesis.

Methods for the design and synthesis of ligands intended to be specific for a metal ion have been a recent chemical development. This article describes how this process can be inverted so that the specifics of the coordination environment around the metal ion can be used as a template in large-scale ligand synthesis. The synthesis of macrobicyclic ligands for ferric ion has been accomplished by using active esters of catechol ligands in which catecholate coordination to iron is a prelude to the organic chemical reactions that link the coordination subunits together into one ligand system surrounding a central metal ion coordination site. The lanthanide(III) ions, which are among the most labile metal ions known, have coordination numbers of 8 or higher, and thus their encapsulation into a macrobicyclic structure is a challenging problem. Lanthanide amine complexes have been used as metal templates in the synthesis of such macrobicyclic lanthanide complexes. There is evidence that such a complex is inert to exchange in aqueous solution.

The spectroelectrochemical determination of the reduction potential of diferric serum transferrin.

The first spectroelectrochemical measurement of the formal reduction potential of iron transferrin has been carried out using methyl viologen to mediate electron transfer to the protein. These calculations take into consideration the weak nature of the ferrous transferrin complex. A value of -0.52(8) V vs. the normal hydrogen electrode was obtained in 0.100 M tris(hydroxymethyl)aminomethane buffer at pH 7.4, 22 degrees C, and 2.0 M KCl. A high ionic strength was necessary to effect reduction, supporting the observation that ions play an important role in the reduction of iron in transferrin. Finally, a procedure for carrying out the reduction of methyl viologen at a gold electrode in a spectrophotometric cell is described.

Ferric ion sequestering agents: kinetics of iron release from ferritin to catechoylamides.

The removal of ferric ion from the iron storage protein ferritin to synthetic catechoylamide sequestering agents has been studied using visible spectroscopy at 487 nm. One ligand which has been investigated in detail is N,N',N' ',-tris(2,3-dihydroxy-5-sulfobenzoyl)-1,5,10-triazadecane (3,4-LICAMS), which octahedrally coordinates the metal ion via six phenolic oxygens. For some related catechoylamide chelates, the percentage of iron removed after 6 h has been determined. These ligands incorporate various modifications, either on the catechol moiety or on the backbone structure of the ligand. Mobilization of iron by the catechoylamide ligands alone results in very slow exchange, and virtually no iron removal after 6 h. In contrast, addition of ascorbic acid to the reaction mixture facilitates iron exchange, with the release of 7% of the available iron in the same time span. Variation of the initial rate with ascorbic acid concentration results in Michaelis-Menten kinetics with Km = 1.7 . 10(-3) M and a maximal rate of 1.28 . 10(-7) M . min-1. The ascorbic acid-mediated rate was not affected by changing the catechoylamide ligand concentration, and was only slightly affected by variation of the ligand employed. These data are consistent with a multistep process which includes diffusion of a reductant into the ferritin inner core, reduction and possible chelation of the ferrous ion, diffusion out of the protein shell, and subsequent iron exchange with the catechoylamide molecule.

Synthetic enterobactin analogues. Carboxamido-2,3-dihydroxyterephthalate conjugates of spermine and spermidine.

Two examples of a new class of synthetic polycatecholate ligands, the carboxamido-2,3-dihydroxyterephthalate conjugates of spermine (8) and of spermidine (10), have been synthesized via the generally useful synthon methyl-2,3-dimethoxyterephthaloyl chloride (6). Initial biological evaluation reveals tetrameric terephthalate (8) to be an extremely effective agent for sequestering and removing plutonium from mice; a single 25-mumol/kg (ip) dose of 8 removed 73% of the plutonium citrate previously injected (iv, 1 h earlier). Under the same conditions, trimeric terephthalate (10) excreted only 49% of injected plutonium. In vitro kinetic experiments have shown that 10 rapidly and quantitatively removed Fe from human transferrin. These results are discussed in relation to the design of metal-ion specific sequestering agents.

Specific sequestering agents for the actinides. 16. Synthesis and initial biological testing of polydentate oxohydroxypyridinecarboxylate ligands.

Chemical and biological similarities of plutonium(IV) and iron(III) suggested that octadentate ligands containing hydroxamate or catecholate functional groups, which are found in microbial iron chelating agents (siderophores), would be effective and relatively selective complexing agents for actinide(IV) ions. However, their usefulness for in vivo chelation of actinide(IV) is limited, because catechol and hydroxamate are such weak acids that the potential for octadentate binding of actinide(IV) cannot be achieved at physiological pH. The structurally similar monoprotic and more acidic 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) group was, therefore, incorporated into multidentate ligands. Treatment of 1,2-dihydro-1-hydroxy-2-oxopyridine-6-carboxylic acid (5) with phosgene in THF solution gives the active ester poly[1,2-dihydro-1,2-dioxopyridine-6-carboxylate], which upon treatment with excess anhydrous dimethylamine gave a 60% yield of N,N-dimethyl-1,2-dihydro-1-hydroxy-2-oxopyridine-6-carboxamide (6). A similarly reactive intermediate was prepared from 5 and an equimolar amount of phosgene in N,N-dimethylacetamide. Combined in situ with 1,3-propanediamine, benzylamine, spermine, spermidine, 1,3,5-tris(aminomethyl)benzene, or desferrioxamine B and excess triethylamine, the latter intermediate gave the corresponding amides in isolated yields ranging from 16% to 60%. The free ligands, their Zn(II) complexes, and the ferric complex of 3,4,3-LIHOPO were administered to mice [30 mumol/kg intraperitoneally 1 h after Pu(IV)-238 citrate, kill at 24 h]. Net Pu removal [Pu excretion (treated)-PU excretion (control)], expressed as percent of injected Pu, was as follows: Na salts and Zn(II) complexes, respectively, of 3-LIHOPO (54, 56), 3,4-LIHOPO (58, 60), 3,4,3-LIHOPO (73, 76); Na salts of MEHOPO (46), DFO-HOPO (78); Fe(III) complex of 3,4,3-LIHOPO (79). DFO-HOPO and 3,4,3-LIHOPO and its Zn(II) and Fe(III) complexes promoted significantly more Pu excretion than CaNa3-DTPA (61% of injected Pu). Preliminary findings on the acute toxicity of the poly(HOPO) ligands and HOPO monomers are presented in an appendix. The biological data indicate strongly that the aqueous solubility and relatively high acidity of the octadentate HOPO ligands, 3,4,3-LIHOPO and DFO-HOPO allow them to form complete eight-coordinate complexes with Pu(IV) ion.

Specific sequestering agents for the actinides. 28. Synthesis and initial evaluation of multidentate 4-carbamoyl-3-hydroxyl-1-methyl-2(1H)-pyridinone ligands for in vivo plutonium(IV) chelation.

A new family of chelating agents based on 4-(substituted-carbamoyl)-3-hydroxy-2-pyridinones is reported. These have optional terminal substituents on the nitrogens, and the hydroxypyridonate (HOPO) rings are attached to molecular backbones through amide linkages. A very important feature of the methyl-substituted ligand derivatives (Me-3,2-HOPOs) is that, similarly to the catechoylamide complexes of the siderophore enterobactin and its analogs, these HOPO derivatives form strong hydrogen bonds between the amide proton and the adjacent oxygen of the phenolate in the metal complex; this enhances the stability of the complex. This rigidity helps to explain the great affinity of the Me-3,2-HOPO ligands for plutonium(IV), as observed here under physiological conditions. All 13 compounds studied significantly enhanced Pu excretion from mice compared with Pu-injected controls. Eight of the ligands studied promoted significantly more Pu excretion than an equal molar amount of CaNa3-DTPA (the compound in present clinical use). Five injected and two orally administered Me-3,2-HOPO ligands promoted as much or slightly more Pu excretion than an equal molar amount of the octadentate 3,4,3-LI(1,2-HOPO), the previously most effective in vivo ligand. Surprisingly, although plutonium has an eight-coordination requirement, tetra- and hexadentate Me-3,2-HOPO ligands were essentially as effective as the one octadentate ligand studied. These observations suggest that even the tetradentate Me-3,2-HOPO ligands compete with mammalian transferrin for Pu(IV). For the three most promising compounds, there is no acute toxicity seen up to the highest dose administered, which was 1000 mumol/kg. One compound, the hexadentate TREN-(Me-3,2-HOPO), is particularly effective, either injected or orally, and an exceptionally good in vivo chelator of several actinides in addition to Pu(IV). Three of these compounds studied have low toxicity and are relatively simple and inexpensive to prepare. They are promising therapeutic agents.

Specific sequestering agents for the actinides. 21. Synthesis and initial biological testing of octadentate mixed catecholate-hydroxypyridinonate ligands.

The linear octadentate ligand 3,4,3-LIHOPO, which contains four 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) groups, is the most effective agent for in vivo chelation of Pu(IV) yet prepared. However, its clinical potential is limited by acute toxicity of the free ligand (but not Fe3+ complex) at high dosage. The high acidity of HOPO ligands and the much lower acidity of catechol (CAM) ligands suggested that mixed octadentate (CAM-HOPO) ligands containing one or two 1,2-HOPO and three (or two) catechol (CAM) groups might be as effective for Pu removal [fully eight-coordinated Pu(IV) complexes formed at pH > or = 6] and less toxic than 3,4,3-LIHOPO. Treatment of spermine with 3-(2,3-dimethoxybenzoyl)thiazol-idine-2-thione (1) (molar ratio 2:1) gave 1,14-bis(2,3-dimethoxybenzoyl)-1,5,10,14-tetraazatetradecane (2, DiCAM-spermine) in 80% yield. Addition of 2 to a 2-fold excess of the reaction product of 1-hydroxy-2-pyridone-6-carboxylic acid (HOPO-C) and 1,1'-carbonyldiimidazole (CDI) in N,N-dimethylformamide (DMF) and deprotection with BBr3 gave 1,14-bis(2,3-dihydroxybenzoyl)-5,10-bis(1-hydroxy-2-pyridon-6-oyl) -1,5,10,14-tetraaza-tetradecane [3, 3,4,3-LI(diCAM-diHOPO)] in 5% yield. Addition of 2 to an equimolar amount of the reaction product of HOPO-C and CDI in N,N-dimethylacetamide (DMAA), purification of the hexadentate intermediate, subsequent treatment with an equimolar amount of 2,3-dimethoxybenzoyl chloride (DMB), and deprotection with BBr3 gave 1,5,14-tris(2,3-dihydroxybenzoyl)-10-(1-hydroxy-2-pyridon-6-oyl)-1 ,5,10,14- tetraazatetradecane [4, 3,4,3-LI(triCAM-HOPO)] in 5% yield. Ligands were administered to mice [30 mumol kg-1 ip at 1 h or orally at 3 min after iv injection of plutonium(IV)-238 citrate, kill at 24 h]. Plutonium excretion after injection of either CAM-HOPO ligand was 700% of that for 24-h Pu-injected controls, 140% of that for mice given the tetracatecholate analogue 3,4,3-LICAM (significantly more, p < 0.01), but only 80% of that promoted by 3,4,3-LIHOPO (significantly less). Orally administered 3,4,3-LI-(diCAM-diHOPO) promoted significantly more Pu excretion than an equimolar amount of CaNa3DTPA. Potency of the CAM-HOPO ligands for in vivo chelation of Pu(IV) resembled that of structurally hexadentate tris-(hydroxypyridinonate) and tris(sulfocatecholate) ligands and functionally hexadentate tetrakis-(sulfocatecholate) and tetrakis(carboxycatecholate) ligands. The Pu complexes of the CAM-HOPO ligands are to some degree unstable at pH < 7.4, as judged by Pu residues in kidneys in excess of 24-h Pu-injected controls. Synthetic yields were insufficient for chemical investigations or evaluation of acute toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Use of tricatecholamide ligands to alter the biodistribution of gallium-67: concise communication.

The effect of the intravenous administration of the synthetic siderophore LI-CAM-C on the biodistribution of Ga-67 was investigated. The ligand was found capable of the in vivo complexing with Ga-67, which hastened the renal clearance of the nuclide. The gallium concentration was decreased in all organs, with the exception of the liver and spleen, where we suggest that hydroxide precipitates interfere with gallium sequestration by LICAM-C. The gallium in abscess tissue was only slightly affected, giving rise to an increase in the Ga-67 abscess-to-soft-tissue concentration ratio when LICAM-C is administered. Dosimetry calculations show that the siderophore decreases the radiation burden from Ga-67 citrate. The advantage of clinical application of LICAM-C are discussed.

Tricatecholamide analogs of enterobactin as gallium- and indium-binding radiopharmaceuticals.

Isopropyl N-substituted tricatecholamide analogs of enterobactin have been found to form gallium and indium complexes with very high stability constants and to exhibit in vivo characteristics significantly different from gallium- or indium-transferrin and EDTA. The 3,4-DiP-LICAMS and TiP-MECAMS complexes were found to clear primarily through the kidneys, whereas the less polar 3,4-DiP-LICAM complex was eliminated through the liver. The rationale for developing new metal-binding analogs with larger organic groups attached to the amide nitrogens is discussed.

Specific sequestering agents for the actinides: 10. Enhancement of 238Pu elimination from mice by poly(catechoylamide) ligands.

Macromolecules containing four sulfonated catecholy (2,3-dihydroxybenzoyl) groups are effective for decorporation of newly acquired Pu(IV). However, multiple injections in mice and single injections in dogs of 30 mumole/kg of 3,4,3-LICAM(S), the most effective sulfonated poly(catechoylamide) ligand, indicated that it would be toxic, so the ligand structure was modified. Each ligand was injected into mice (30 mumole/kg, intraperitoneally) 1 hr after an intravenous injection of 238Pu(IV) citrate, and mice were killed 24 hr after the Pu injection. Excreta and tissues were analyzed for Pu. (a) The number of catechoyl groups per molecule was reduced to suppress affinity for Fe(III). Net excretion (treated - control) of 55% of the injected Pu was promoted by tetrameric 3,4,3-LICAM(S), 51% by trimeric 3,4-LICAM(S), 22% by dimeric 2-LICAM(S), and 7.4% by the monomer, Tiron. (b) A mesitylene platform was substituted for the linear backbone. Net Pu excretion promoted by MECAM(S), a structurally less flexible trimer, was only 26%, and excretion was delayed. (c) A carboxyl substituent on the catechoyl groups reduced the acidity and hydrophilicity of the ligands. Tetrameric 3,4,3-LICAM(C) promoted 63% net Pu excretion, and one-third of that was fecal. The Pu contents of liver and skeleton were 33 and 44% of their respective 1-hr control values--compared to 51 and 44%, respectively, for CaNa3-DTPA. Mice given 30 mumole/kg of 3,4,3-LICAM(C) 20 times in 4 weeks showed no ill effects. (d) Large N-terminal alkane substituents added to 3,4,3-LICAM(C) increased ligand lipophilicity, hindered Pu chelation, and delayed excretion.

A streamlined synthesis for 2,3-dihydroxyterephthalamides.

[reaction: see text]. 2,3-Dihydroxyterephthalamides have been synthesized through a route that avoids the protection and deprotection of the phenol groups. The procedure allows for symmetric and unsymmetric amide linkages. This synthetic sequence significantly decreases the time and cost of preparation and increases the overall yield of this class of metal chelators.

Multidentate hydroxypyridinonate ligands for Pu(IV) chelation in vivo: comparative efficacy and toxicity in mouse of ligands containing 1,2-HOPO or Me-3,2-HOPO.

PURPOSE: To identify the most effective multidentate 1,2-HOPO and Me-3,2-HOPO ligands for chelation of Pu(IV) in vivo. MATERIALS AND METHODS: Two sets of ligands with four identical backbones were prepared containing two, three or four bidentate 1,2-HOPO or Me-3,2-HOPO groups, and 3,4,3-LI(1,2-HOPO) was resynthesized in a higher yielding procedure. They were evaluated in mouse for acute toxicity and reduction of tissue 238Pu, in comparison with CaNa3-DTPA (30 micromol kg(-1)). RESULTS: Nine HOPO ligands, promptly injected or given orally or injected at low dosage, are superior to CaNa3-DTPA for reducing 238Pu retention in mouse. Five, given by delayed injection or promptly injected or orally administered as ferric complexes, are superior to CaNa3-DTPA or FeNa2-DTPA respectively. The Me-3,2-HOPO ligands are more effective than their structural 1,2-HOPO analogues, demonstrating the greater affinity of Me-3,2-HOPO for Pu(IV) in vivo. CONCLUSIONS: The most efficacious ligand, 3,4,3-LI(1,2-HOPO), contains the less stably binding 1,2-HOPO group; therefore, its linear spermine backbone must confer advantages for Pu(IV) binding (greater solubility, more favorable arrangement of ligating groups, more flexible backbone). Effective low toxicity tetradentate 5-LIO(Me-3,2-HOPO) and hexadentate TREN-(Me-3,2-HOPO) and highly effective but moderately toxic 3,4,3-LI(1,2-HOPO) (LD50 approximately 300 micromol kg(-1) in mouse) are recommended for further investigation.

Early chelation therapy for injected Pu-238 and Am-241 in the rat: comparison of 3,4,3-LIHOPO, DFO-HOPO, DTPA-DX, DTPA and DFOA.

Chelating agents were tested for removal of simultaneously injected Pu-238 and Am-241 from the rat. The effectiveness of early single chelate injections of Pu-238 retention in tissues decreased in the order 3,4,3-LIHOPO > DFO-HOPO > DTPA > DTPA-DX, and for Am-241 in the order 3,4,3-LIHOPO > DTPA-DX > DTPA >> DFO-HOPO. DTPA-DX showed a special ability to remove Am-241 from the liver. Injected 3,4,3-LIHOPO decreased the contents of Pu-238 in bone and liver to 9 and 3%, respectively, of those in untreated controls. Corresponding values for Am-241 in bone and liver were 30 and 6%, respectively, which indicates that 3,4,3-LIHOPO (unlike DFO-HOPO) is not a plutonium-specific chelator. The effectiveness of prompt single oral treatment with 3,4,3-LIHOPO and DFO-HOPO in reducing retention of actinides was comparable with that of those chelators injected with 1 h delay and at one-third of the oral dose. When 3,4,3-LIHOPO was administered by continuous infusion, a superior effect was achieved with total chelate amounts only slightly exceeding that given as single injection. The retention of PU-238 and Am-241 in bones was reduced to < 5 and 10% of controls, respectively; the contents in the liver were < 2% of controls.

Chelation therapy by DFO-HOPO and 3,4,3-LIHOPO for injected Pu-238 and Am-241 in the rat: effect of dosage, time and mode of chelate administration.

The effectiveness of the siderophore analogues DFO-HOPO (a hydroxypyridone derivative of desferrioxamine) and 3,4,3-LIHOPO (a linear tetrahydroxypyridinone) for the decorporation of 238Pu and 241Am from rat was studied. (1) Dosage-effect relationship. A similar treatment effect on Pu was achieved by single s.c. injection of 30 mumol kg-1 or by oral administration of 100 mumol kg-1 of either of the two ligands, provided the oral dose was administered earlier. In general, LIHOPO was more effective than DFO-HOPO: retention of Pu in the liver and bones was reduced by LIHOPO to < 10% of control values. No increase in renal retention of the actinides was observed. Whilst DFO-HOPO did not affect Am retention, a substantial reduction was achieved by LIHOPO. Removal effectiveness for injected LIHOPO on Pu was higher than that on Am, especially in the bones and after low ligand doses. Orally administered small doses of LIHOPO, however, mobilized more Am than Pu, both from the liver and the bone. (2) Time-effect relationship. The effectiveness of the injected ligands for Pu decreased exponentially with the time between exposure and treatment. With DFO-HOPO, the calculated half-times for decrease of mobilized fractions of Pu from the bone and liver were 5 and 12 h respectively. The effect of LIHOPO on Pu decreased much more slowly, with a half-time of 3-4 weeks. For instance, a single injection of 30 mumol kg-1 LIHOPO at 10 days post-Pu removed 30 and 50% activity from the bone and liver respectively. The removal effect of LIHOPO for Am in the liver decreased with time in the same way as for Pu but the mobilized fractions of skeletal and renal Am decreased from the first day with a half-time of only 8 and 4 days respectively.

Treatment with 3,4,3-LIHOPO of simulated wounds contaminated with plutonium and americium in rat.

The effect of a siderophore analogue 3,4,3-LIHOPO has been investigated in rat after intramuscular injection of 238Pu, 239Pu and 241Am simulating puncture wounds. Various treatment regimens were used to remove the radioactivity from its injection site and to reduce its retention in body tissues. The local deposits could be reduced to 9% of that in untreated controls by a single local injection of 30 mumol kg-1 3,4,3-LIHOPO administered 1 day after the actinides. Tissue retention of radioactivity was most effectively reduced (to 3% of controls) by continuous subcutaneous infusion of 3,4,3-LIHOPO (3 mumol kg-1 day-1), starting immediately after the injection of actinides and continuing for 2 weeks. The administration of 3,4,3-LIHOPO in drinking water was least effective. Treatment efficacy was substantially higher with 238Pu than with an equal activity of 239Pu (the 238Pu mass, however, was almost 300 times lower than that of 239Pu). Accordingly, the biokinetics and removal of 241Am changed when it was injected with 239Pu instead of 238Pu. Continuous infusion of 3,4,3-LIHOPO (3 mumol kg-1 day-1), starting 4 and 30 days after intramuscular injection of 238Pu and 241Am reduced their femoral retention after 1 month to 20 and 60% of controls respectively; whole-body retention of 241Am was reduced to 20 and 70% of controls respectively.

Efficacy of 3,4,3-LIHOPO for reducing the retention of 238Pu in rat after inhalation of the tributyl phosphate complex.

The efficacy of 3,4,3-LIHOPO, a siderophore analogue, has been tested for removing 238Pu from rat after inhalation of plutonium as the tri-N-butylphosphate (TBP) complex. The amounts of Pu retained in the lung of untreated rat, 7 days after exposure ranged from 0.86 to 37 kBq. The results have been compared with DTPA, the current therapy of choice for man. The ligand 3,4,3-LIHOPO was more effective than DTPA for removing Pu from the body when repeated treatment began 1 h after inhalation. This observation was independent of the mass of Pu deposited in the lungs. The efficacy of 3,4,3-LIHOPO was mainly due to the decrease of Pu retention in lung, 1.5 times less than after DTPA administration; in liver and skeleton, retention was about four times less. Seven days after internal contamination, < 10% of the activity was found in organs other than lung when rat was treated with 3,4,3-LIHOPO. As this ligand showed an apparent lack of irreversible toxicity, it is likely to be of interest in the development of new decorporation treatments after inhalation of Pu as a TBP complex.

Efficacy of 3,4,3-LIHOPO for enhancing the excretion of plutonium from rat after simulated wound contamination as a tributyl-n-phosphate complex.

The siderophone analogue 3,4,3-LIHOPO, referred to hereafter as LIHOPO, has been examined for its ability to remove 238Pu in a tributyl-n-phosphate (TBP) complex from rat after intramuscular (i.m.) or subcutaneous (s.c.) contamination. The chelating agent was administered at a dosage of 30 mumol.kg-1, 30 min after the contamination, either by intravenous (i.v.) or local injection. By day 7 after exposure, local (i.m.) administration of LIHOPO reduced the amounts of i.m.-injected 238Pu in the would site, skeleton and liver to 75, 20 and 25% respectively of those in untreated animals. At the i.m. Pu would site, local treatment was superior to i.v. treatment; both ligands were equally effective. At the s.c. Pu would site, local and systemic treatments were equally effective and LIHOPO was superior to DTPA. After translocation, LIHOPO was the most effective treatment for enhancing Pu excretion, whatever the route of contamination and treatment: the administration of LIHOPO and DTPA reduced whole-body Pu retention by a factor of 1.8 and 1.4 respectively. All these results are encouraging for the use of LIHOPO in the future but more studies are needed, concerning both the toxicity of the compound and its use in man.

Efficacy of 3,4,3-LIHOPO for reducing neptunium retention in the rat after simulated wound contamination.

PURPOSE: The ligand 3,4,3-Li(1,2-HOPO) was tested for Np removal after intramuscular injection of 237Np nitrate in rats. MATERIALS AND METHODS: Two experiments were performed, one with simultaneous injection of neptunium and LIHOPO at dosages ranging from 3 to 200 micromol kg(-1) and the other with delayed administration of LIHOPO 30 micromol kg(-1) from 5 min to 30 min after Np injection. RESULTS: The data obtained after simultaneous injections showed that the ligand dosage effectiveness was not linear and depended on the tissues being considered. For bones, the best results were obtained with 200 micromol kg(-1) LIHOPO, where retention was reduced to 11% of controls. Maximum efficacies for removal in liver and kidney were obtained with 30 micromol kg(-1) LIHOPO, where retention was reduced to 39% and 1.6% of controls, respectively. At higher dosages, LIHOPO seemed to have a reverse effect on these tissues, demonstrated by a significant accumulation of the radionuclide. The delayed administration of LIHOPO dramatically decreased its efficacy. When administered 5 min after Np, LIHOPO was still efficient (60%, 37%, 7% of controls in bone, liver, kidneys, respectively) but not when treatment was delayed to 30 min. CONCLUSIONS: These results demonstrated that LIHOPO was able to complex Np at the wound site but not after translocation to blood.

The efficacy of DFO-HOPO, DTPA-DX and DTPA for enhancing the excretion of plutonium and ameriicum from the rat.

A hydroxypridinone derivative of desferrioxamine (Na-DFO-HOPO), a dihydroxamic derivative of diethylenetriaminepenta-acetic acid (ZnNa-DTPA-DX), and DTPA (CaNa3- and ZnNa3-DTPA) were tested at dosages of 30 mumol kg-1 for their ability to remove 238Pu or 241Am from rats after their intravenous injection as citrate or inhalation as nitrate. The most effective treatment regimen for injected Pu was the repeated administration of DFO-HOPO; by 7 days the body content was reduced to 8% of that in untreated animals. Repeated dosages of 3 mumol kg-1 DFO-HOPO were as effective as those of 30 mumol kg-1 DTPA. After inhalation of Pu nitrate, repeated treatment with DTPA, DTPA-DX or DFO-HOPO reduced the body content by 7 days to, respectively, 10, 15 and 31% of those in untreated animals. After inhalation of Am, DTPA-DX and DTPA were equally effective, the body contents being reduced to 7% of control values with repeated treatment. Injection of DFO-HOPO was ineffective for enhancing the elimination of inhaled or injected Am. The results confirm the strategy of examining the use of siderophore analogues for the decorporation of Pu or Am. However, at present DTPA should remain the agent of choice, particularly after inhalation.

Comparative efficacies of 3,4,3-LIHOPO and DTPA for enhancing the excretion of plutonium and americium from the rat after simulated wound contamination as nitrates.

With DTPA as a comparison, the siderophore analogue 3,4,3-LIHOPO has been examined for its ability to remove 238Pu and 241Am from the rat after subcutaneous (s.c.) and intramuscular (i.m.) injection of about 200 Bq of each actinide (0.3 ng Pu, 1.6 ng Am). After the s.c. deposition of 238Pu and 241Am, both ligands were more effective after local administration than (in decreasing order) their repeated interperitoneal (i.p.) injection, single i.p. injection and continuous infusion. Dosages of 3 mumol kg-1 of 3,4,3-LIHOPO were at least as effective as 30 mumol kg-1 DTPA after each mode of administration. The most effective regimen of those investigated for s.c. 238Pu and 241Am involved local administration of 30 mumol kg-1 of 3,4,3-LIHOPO at 30 min followed by i.p. injections at 6 h, 1, 2 and 3 day. By day 7 after exposure, the amounts of 238Pu and 241Am retained in the body were 2 and 7% of those in controls, respectively and 10 and four times less than when DTPA was administered using the same regimen. The ligand 3,4,3-LIHOPO was more effective for 238Pu and 241Am after their i.m. injection. This was attributed to the greater retention of these actinides at the wound site (97 versus 67%) when treatment commenced. After a single local injection of 30 mumol kg-1 at 30 min, the amounts of 238Pu and 241Am retained in the body at 7 day were 0.9 and 0.8% of controls. These values were 34 and 27 times less than after local and repeated i.p. injections of DTPA at dosages of 30 mumol kg-1. It is concluded that the administration of 3,4,3-LIHOPO represents potentially a most significant advance in the treatment of wound contamination by 238Pu and 241Am by chelating agents.