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The nature and rates of excretion of radioactive breakdown products of I131-albumin in the rabbit.

When I(131)-albumin is given intravenously to rabbits, the radioactive breakdown products that are released into the plasma and urine can be extracted into acetone. Paper chromatography and paper electrophoresis show that about 80 per cent of these are I(131)-iodide and the remainder are organic I(131)-iodine compounds. When I(131)-iodide is given to rabbits taking iodide in their drinking water, the radioactivity is quantitatively excreted, without being accumulated in the tissues and without becoming attached to the plasma proteins. The rate of excretion can be defined by a first order rate process with a rate constant, a, ranging between 1 and 3day(-1). The organic I(131)-iodine compounds liberated during the metabolism of I(131)-albumin can be closely matched by a mixture of the organic I(131)-iodine compounds liberated during the metabolism of I(131)-monoiodotyrosine, I(131)-diiodotyrosine, and the amino acids released by digestion from I(131)-albumin. These organic I(131)-iodine compounds are not accumulated in the body and their radioactivity does not become attached to the plasma proteins. Their radioactivity is excreted as fast or faster than that of I(131)-iodide, and, to a satisfactory approximation, the same equations describing the excretion of I(131)-iodide with the same constants may be used for describing the excretion of the organic I(131)-iodine. These results permit improved estimates of the distribution and catabolism of I(131)-albumin.

Animals↗

Iodination of p-nitrophenyl ethers used as photolabels.

A system for radioactive labeling of compounds of biological interest that, due to their low electronic density, cannot be labeled by the standard iodination techniques is described. Using p-nitroanisole as a model, we have prepared 2-[125I]iodo-4-nitroanisole by treatment with thallium trifluoroacetate, with later displacement of the thallium by iodide according to A. McKillop et al. (J. Amer. Chem. Soc. 93, 4841-4844 (1970)). The labeled iodonitroanisole has been used as a photoactive reagent to label a protein (bovine serum albumin), showing that under the irradiation conditions used, the label is incorporated into the polypeptide mainly through modification of epsilon-amino groups of the lysine residues.

Anisoles↗

Blood-brain barrier, half-time disappearance, and brain distribution for labeled enkephalin and a potent analog.

The natural opiate methionine-enkephalin and its D-alanine2 analog were iodinated by a method involving lactoperoxidase and purified by partition chromatography on Sephadex G-25. The half-time disappearance of radioactivity was determined in blood obtained from the jugular vein after injection of the iodinated methionine-enkephalin into the carotid artery or jugular vein and found to be less than a minute. Despite a greater potency and more prolonged activity of D-alanime2-methionine-enkephalin as compared with methionine-enkephalin, the half-time disappearance of radioactivity after injection of the iodinated analog was about the same, its distribution volume tended to be smaller, and the retention of counts in the brain was significantly less then after the iodinated parent compound. There was little statistical difference in the accumulation of radioactivity among nine brain regions 5 sec after the rapid injection of tritiated methionine-enkephalin into the carotid artery in contrast with the accumulation found after similar injection of tritiated tyrosine or tritiated water. The ratio of radioactivity in the pituitary or pineal to that in the brain parts within the blood-brain barrier was much greater after administration of the tritiated enkephalin than after the tritiated water. A modified brain-uptake index (BUI) value of 15 for the tritiated enkephalin indicates that methionine-enkephalin crosses the blood-brain barrier.

Animals↗

New radionuclide tracers for the diagnosis and therapy of medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC), a calcitonin-producing tumor that occurs in familial and sporadic forms, can be monitored satisfactorily with measurements of calcitonin and CEA in serum. However, locating the tumor site may be difficult. In the current review of the experience with four new radionuclide tracers for MTC, the relative value of each of these procedures is outlined. Total body imaging using TI-201 chloride and Tc-99m(V) DMSA are both sensitive techniques that can be used for the detection and follow-up of MTC. Imaging using I-131 MIBG and I-131 anti-CEA antibodies/fragments should be performed once the diagnosis and the tumor site have been established, to evaluate if patients might be amenable for therapy with one of these radiopharmaceuticals.

3-Iodobenzylguanidine↗

Stimulation of monocyte iodination and IL-1 production by tannins and related compounds.

Various tannins and related compounds were compared for their ability to stimulate the iodination (incorporation of radioactive iodine into an acid-insoluble fraction) of human peripheral blood monocytes. The stimulating activity of most of the monomeric and dimeric hydrolyzable tannins was generally higher than that of the trimeric and tetrameric compounds. Compounds that had dehydrohexahydroxydiphenoyl or chebuloyl groups had considerably less activity than those that had other functional groups (hexahydroxydiphenoyl, valoneoyl, dehydrodigalloyl, isodehydrodigalloyl, lactonized valoneoyl, hellinoyl, euphorbinoyl, dehydroeuphorbinoyl or woodfordinoyl group). The methylated derivative, nonacosa-O-methylcoriariin A, was essentially inactive, suggesting the requirement of a phenolic hydroxyl group. Three condensed tannins ((-)-epicatechin 3-O-gallate (ECG)-dimer, ECG-trimer and ECG-tetramer) significantly stimulated both monocyte iodination and their interleukin-1-like factor production. The results suggest the dependence of stimulation of monocyte iodination by tannins and related polyphenols on molecular weight.

Animals↗

Synthesis of photoactivable inhibitors of osteoclast vacuolar ATPase.

Amides of (2Z,4E)-5-[(5,6-dichloroindol-2-yl)]-2-methoxy-N-[3-[4-[3-(carboxymethoxy)phenyl)] piperazin-1-yl]propyl]-2,4-pentadienamide (1) and of 5-(5,6-dichloro-2-indolyl)-2-methoxy-2,4-pentadienoic acid (2) are strong inhibitors of the vacuolar ATPase located on the plasma membrane of osteoclasts. In order to understand which V-ATPase subunit is involved in the interaction with these novel inhibitors, analogues containing a photoactivable group and an iodine atom were designed. A series of alcohols or amines containing the photoactivable trifluoroaziridinophenyl or benzophenone moiety and an iodine atom were linked to the above acids via an ester or amide group. These compounds could be thereafter used as a radioactive photoprobe to label the protein. Whereas the compounds containing the photoactivable groups maintained good inhibitory activity, the introduction of the bulky iodine atom was generally detrimental, decreasing potency significantly. Better results were obtained by linking 3-(4-aminopiperidinomethyl)-3'-iodobenzophenone to 3-ethoxy-4-(2-(5,6-dichlorobenzimidazolyl))benzoic acid to give the corresponding amide 27, that inhibited vacuolar ATP-ase with a IC(50)=140 nM. The feasibility of introducing a radioactive 125I atom was ascertained by exchanging the iodine with a tributylstannyl group, that was again substituted by iodine.

Amides↗

The lymphatic and venous pathways for the outflow of thyroxine, iodoprotein and inorganic iodide from the thyroid gland.

1. Baboons and cats were given radioactive iodine and, at varying times after the injection, samples of thyroid and non-thyroid lymph and of thyroid venous and peripheral venous blood were collected. The radioactive material in these samples was separated by paper chromatography or by differential precipitation and solvent extraction into three main fractions: inorganic iodide, iodoamino acid iodine and high molecular-weight material (retained at the origin of chromatograms and not extractable by butanol or ethanol). The latter was considered to be iodoprotein.2. Thyroxine was the main component of the radioactive iodoamino acid iodine in thyroid lymph, in thyroid venous and in peripheral blood. The concentration of thyroxine radioactivity in the thyroid lymph was several times greater than that in either thyroid venous or peripheral blood plasma, both before and after giving thyroid stimulating hormone.3. An unidentified thyronine compound that was frequently found in thyroid lymph and also in blood samples contained an appreciable proportion of the radioactive iodine. This substance was probably a metabolite of one of the iodothyronines. In addition, iodotyrosines probably accounted for up to 4% of the radioactivity in the lymph and blood samples but radioactive triiodothyronine could not be detected with certainty.4. In some experiments lymph was obtained from the cervical lymph trunk at a considerable distance from the thyroid gland, in order to avoid operative trauma to the gland. This cervical lymph contained diluted thyroid lymph but even so it contained more radioactivity in the form of iodoamino acid and iodoprotein than did peripheral blood or non-thyroid lymph. Cervical lymph and thyroid lymph both contained less radioactive inorganic iodide than did non-thyroid lymph.5. The administration of thyroid stimulating hormone caused a prolonged rise in the output of radioactive iodoamino acid in the thyroid venous blood and, for a limited period, an increase in the output of radioactive inorganic iodide. At the same time there was an increase in the output of radioactive material in the thyroid lymph. The main part of the latter was due to a rise in the output of iodoprotein.6. The lymphatics and the venous system provide alternative pathways for the outflow of iodine compounds from the thyroid gland. These pathways differ in relative importance for different iodine compounds. For iodoprotein the lymphatic pathway is the important one since there is no appreciable release of this substance into the thyroid venous blood. In the case of inorganic iodide, where there is no appreciable difference in concentration between thyroid lymph and blood, the greater flow of blood makes the venous pathway relatively more important than the lymphatic one. Thyroxine is released into the thyroid lymph in higher concentration than into the blood but the faster flow of blood makes the venous pathway relatively more important.

Animals↗

Further studies of the metabolism of thyroxine and 3,5,3'-triiodothyronine in the guinea-pig.

1. Thyroxine labelled with (125)I and triiodothyronine labelled with (131)I have been administered simultaneously to guinea-pigs and their metabolism studied by whole body counting and measurement of radioactivity in urine, faeces, and blood.2. The half-life of triiodothyronine in the body is about 19 hr, significantly less than that of thyroxine (41 hr).3. After triiodothyronine administration, an unidentified iodinated compound appears in the blood which complicates the estimation of the half-life of this hormone by measurement of the radioactivity in peripheral blood.4. A previous report, based on measurements of blood radioactivity, that the half-lives of the two hormones are similar in the guinea-pig was not confirmed.

Animals↗

[Pharmacokinetics of benziodarone labelled with I-131].

Regarding the importance of benziodarone (Retrangor) -- 2-ethyl-3-(3',5'-diiodo-4'-hidrovibenzoyl)benzofuran -- in medical practic, in respect of its vasodilator and uricosuric action, a working plan was developed intending to study the biological distribution of the drug in rats Wistar and, using the plasmatic curve, to find out the existence of other compartements besides the intravascular one. With these data, the rhytms of benziodarone exchange were established, simulating its distribution in the organism. It was possible to develop this working project because the benziodarone structure could be labelled with iodine-131, using an isotopic exchange reaction, having chloramine T as an oxidant agent. The labelled compound was employed as radioactive tracer, and its specific activities varied from 18 uCi/mg to 20 uCi/mg.

Animals↗

Closo-dodecaborate(2-) as a linker for iodination of macromolecules. Aspects on conjugation chemistry and biodistribution.

Boron-containing compounds like closo-dodecaborate(2-) are in theory suitable for radioactive labeling with halogens. The boron-halogen bond is stronger than carbon-halogen bond and is not likely to be recognized by deiodinating enzymes in vivo. Peptides and proteins may be conjugated with various closo-dodecaborate(2-)-containing ligands, and thereafter, the conjugate can be iodinated. Since closo-dodecaborate(2-) is more avidly iodinated than tyrosine in moderately acidic media, such conjugates may be directly labeled on the boron part with radioisotopes of iodine using the standard Chloramine-T procedure. Mercapto-undecahydro-closo-dodecaborate(2-) (BSH) was reacted with the double bond of allyldextran to form a boronated dextran compound of the molecular size of about 70 kDa. This compound, in the text denoted as Dx-BS, and cesium dodecahydro-closo-dodecaborate(2-) were labeled using iodine-125. The two compounds were administered to rats in order to study their in vivo stability. The results indicate that iodinated Dx-BS is stable for about 20 h in vivo. The degradation rate, as indicated by thyroid uptake, was found low. [125I]Iodo-closo-dodecaborate(2-), which is a possible degradation product of [125I]Dx-BS-I, was rapidly excreted in urine without significant accumulation in any organ.

Animals↗

Radioactive colloidal solutions and suspensions for medical use.

Radioactive colloidal solutions and suspensions are being widely used in the diagnosis and treatment of various diseases. The author considers the behaviour or radioactive disperse preparations in the body and devotes particular attention to the reasons for isotope transition from the colloidal to the ionic state. Questions concerned with producing and investigating radioactive colloidal solutions are discussed. In the light of the physical and chemical properties of the radioisotopes and of the disperse systems themselves, the author considers methods of producing the more important radioactive disperse preparations: colloidal solutions of noble metals; colloidal solutions containing phosphorus-32, yttrium-90 and isotopes of the rare-earth elements; colloidal solutions with with indium-113m, gallium-68, technetium-99m and rhenium-186; suspensions (macroaggregates and microspheres) for the diagnosis of lung diseases; and radioactive colloidal solutions based on quaternary ammonium base compounds.

Colloids↗

Transport of bovine milk xanthine oxidase into mammary glands of the rat.

This research investigated transport of bovine milk xanthine oxidase into mammary glands of the lactating rat. Transport capability suggested an exogenous, nonmammary, source for the enzyme. Five lactating rats were injected intracardially with 100 microgram of purified iodine-125 labeled xanthine oxidase and five were injected with 100 microgram of the enzyme unpurified. Four hours later the rodents were hand-milked, and radiation was confirmed in all samples by liquid scintillation counting. Counts were recorded per volume of milk and the percentage radiation was computed. Autoradiographs of the rats indicated radiation almost exclusively associated with the mammary glands. Greatest concentration of radioactivity was in the micellar casein fraction of milk, and a compound of high molecular weight, presumably [iodine-125]xanthine oxidase, was confirmed by gel filtration of the casein. Results suggest that the compound was transported into the mammary glands. The degree of transport was dependent upon the stage of lactation.

Animals↗