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Radiation dose rates from adult patients undergoing nuclear medicine investigations.

Adult patients undergoing nuclear medicine investigations may subsequently come into close contact with members of the public and hospital staff. In order to expand the available dosimetry and derive appropriate recommendations, dose rates were measured at 0.1, 0.5 and 1.0 m from 80 adult patients just before they left the nuclear medicine department after undergoing one of eight 99Tcm studies, an 123I thyroid, an 111In leucocyte or a 201Tl cardiac scan. The maximum departure dose rates at these distances of 150, 30 and 7.3 microSv h-1 were greater than those found in similar published studies of adult and paediatric patients. To limit the dose to an infant to less than 1 mSv, an 111In leucocyte scan is the only investigation for which it may be necessary to restrict close contact between the infant and a radioactive parent, depending on the dose rate near the surface of the patient, the parent's habits and how fretful is the infant. It is unlikely that a ward nurse will receive a dose of 60 microSv in a working day if caring for just one radioactive adult patient, unless the patient is classified as totally helpless and has undergone a 99Tcm marrow, bone or brain scan. The data and revised calculations of effective exposure times based on a total close contact time of 9 h in every 24 h period should allow worst case estimates of radiation dose to be made and recommendations to be formulated for other circumstances, including any future legislative changes in dose limits or derived levels.

Adult↗

Characterization of a membrane receptor for transforming growth factor-beta in normal rat kidney fibroblasts.

A procedure has been developed for the iodination of human transforming growth factor-beta (TGF-beta) with full retention of biological activity. Using the iodinated peptide, saturable receptors have been found for TGF-beta on normal rat kidney fibroblasts, a cell line that will grow in soft agar in the presence of TGFs but not in their absence. Scatchard analysis of the binding data showed a high affinity binding site (dissociation constant equal to 25 to 30 pM with approximately 17,000 receptors per cell). The receptor was specific for TGF-beta with epidermal growth factor, insulin, insulin-like growth factors I and II, platelet-derived growth factor, and TGF-alpha being unable to compete for the binding of 125I-TGF-beta to the receptor. The binding of TGF-beta was a time- and temperature-dependent process. At 37 degrees C, maximal binding was attained within 45 to 60 min after addition of 125I-TGF-beta followed by a rapid decline in cell-associated radioactivity due to degradation of the 125I-TGF-beta. As demonstrated using ammonium acetate, a compound known to inhibit lysosomal enzymes, this degradation was most likely due to the action of proteolytic enzymes found in the lysosome. At 0 degrees C, binding reached a plateau within 2 to 3 h and maintained this level with no apparent drop during the 4-h incubation period. The receptor could be down-regulated by TGF-beta, but not by epidermal growth factor, to approximately 50% of the level initially observed.

Binding, Competitive↗

Binding of latamoxef (moxalactam) and its decarboxylated derivative to Escherichia coli and Pseudomonas aeruginosa penicillin-binding proteins.

The binding of latamoxef (moxalactam) and of a decarboxylated derivative to Escherichia coli and Pseudomonas aeruginosa penicillin-binding proteins (PBPs) was measured by competition experiments with 125I-radiolabelled penicillin X. Latamoxef and the decarboxylated derivative were highly bound to most of the PBPs, with the exception of PBP-2. As the two compounds possess a phenolic side-chain, they also could be radiolabelled with 125I. The proteins thus labelled by these derivatives were qualitatively the same as those labelled by 125I-penicillin X, except for PBP-2 which was not labelled by the iodo derivatives of latamoxef and its decarboxylated derivative, and PBP-1c (in E. coli) which is labelled only poorly by the radioactive penicillin. No important difference between latamoxef and its decarboxylated derivative was found, and the same observation was made for penicillin G and carbenicillin. Thus, it was concluded that the carboxylic group of latamoxef does not play an important role in affinity for the targets.

Bacterial Proteins↗

An 125I-labeled binding probe for the muscarinic cholinergic receptor.

We describe the synthesis and characterization of [125I]3-quinuclidinyl-(3-iodo-4-hydroxy-benzilate), a binding probe for the muscarinic cholinergic receptor of high specific radioactivity. The binding isotherm of this 125I-labeled compound to a rat synaptic plasma membrane-enriched fraction consists of two components: a 'specific' component which is saturable and closely fits hyperbolic binding to a single class of sites as evaluated by Scatchard analysis (Kd = 1.5 to 3 nM), and a linear component which may be measured directly by preincubating membranes in 0.1 microM 3-quinuclidinyl-benzilate, the most potent muscarinic antagonist known. The specific binding of [3-3H]3-quinuclidinyl-benzilate and [125I]3-quinuclidinyl-(3-iodo-4-hydroxy-benzilate) to rat brain subcellular fractions is parallel in myelin, synaptic plasma membrane and mitochondrial fractions with a 3--4-fold enrichment observed in synaptic plasma membrane over crude mitochondrial fractions. The concentrations of muscarinic antagonists required to block [125I]3-quinuclidinyl-(3-iodo-4-hydroxy-benzilate) binding parallel that reported for tritiated binding probes and are consistent with physiological measurements of their dissociation constants. Because of the high specific radioactivity of [125I]3-quinuclidinyl-(3-iodo-4-hydroxy-benzilate), this iodinated binding probe should prove useful in assaying low levels of muscarinic receptor in tissue culture and other biological sources.

Animals↗

Metabolic fate of iodine-123-BMIPP in canine myocardium after administration of etomoxir.

UNLABELLED: To clarify the metabolic fate of 123I-(-p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) in dysfunctional myocardium, a comparison between normal dogs and those with etomoxir administration was studied using an open-chest canine model. METHODS: Using open-chested dogs under anesthesia, we created a system to release all the blood in the great cardiac vein outside without recirculation, if necessary. Iodine-123-BMIPP was directly injected into the left anterior descending artery, its extraction, retention and washout rate in the early phase were calculated, and the metabolites in the myocardium were evaluated using a high-performance liquid chromatography. Moreover, these factors were compared between normal dogs and those pretreated with etomoxir, that creates a condition similar to ischemia. RESULTS: Although rapid extraction of BMIPP from the plasma into the myocardium and the subsequent retention were unchanged, early washout (8 min) of radioactivity significantly increased (49.6% +/- 13.3%-->70.5% +/- 10.7%, p < 0.05) with etomoxir. The levels of the full metabolite formed by complete oxidation of BMIPP decreased significantly with etomoxir (21.4% +/- 10.9%-->5.5% +/- 3.5%, p < 0.01). In addition, back diffusion of BMIPP increased (25.1% +/- 8.0%-->41.9% +/- 12.0%, p < 0.05) in the etomoxir-treated animals without affecting the levels of alpha-oxidation metabolite and the intermediate metabolites. CONCLUSION: BMIPP is very sensitive to etomoxir and is suitable for assessing mitochondrial dysfunction. Iodine-123-BMIPP might be a promising radiopharmaceutical for the evaluation of ischemic heart disease, cardiomyopathy and mitochondrial encephalomyopathy.

Animals↗

Preparation of 125I-labeled human growth hormone of high quality binding properties endowed with long-term stability.

125I-labeled human growth hormone (125I-labeled.hGH) was prepared by using two variants of the chloramine T labelling procedure and purified by polyacrylamide gel electrophoresis (PAGE) of the reaction mixture. Variant A produced a tracer with high specific activity (100 +/- 10 microCi/microgram), high maximal binding capacity to antibodies (93%) and long-term stability (at least 150 days at -20 degrees C). No diiodinated tyrosil residues could be detected in this tracer. Variant B was devised to obtain higher yields of labeled hormone. The electrophoresis of the iodination mixture revealed two radioactive components with Rm values of 0.49 and 0.55 which result from the iodination of hGH variants preexisting in the starting material. Both tracers had similar specific activities (70 +/- 10 microCi/microgram), high maximal binding capacity to antibodies or receptors (80-100%, after 80 days of their obtention) and high stability (at least 100 days at -20 degrees C). It is concluded that the iododerivatives of hGH obtained by either method are adequate to perform radioimmunoassay and receptor studies and have long-term stability.

Chloramines↗

Iodine-123 salmon calcitonin, an imaging agent for calcitonin receptors: synthesis, biodistribution, metabolism and dosimetry in humans.

Calcitonin is used to reduce high serum calcium levels in patients with malignancy, and as therapy for osteoporosis and Paget's disease. Receptors for the peptide have been identified in some human cancer cells including those of lung, breast, bone, prostate, and medullary carcinoma of the thyroid, suggesting that an imaging agent for the receptors might be useful in nuclear oncology. A modified chloramine-T method was used to label a pharmaceutical form of salmon calcitonin (SCT) with iodine-123. Labelling can be performed within 5 min including purification, resulting in >95% radiochemical purity and 70% yield. Digestion analysis shows labelling with two iodine atoms on the tyrosine residue. A Chinese hamster ovary cell-based assay showed that the receptor binding and activation were not impaired by the labelling. Biodistribution in mice was similar to that of commercially available mono-iodinated 125I-labelled SCT, kidney being the principal target organ. Evaluation in three patients previously diagnosed as having Paget's disease (injected with 37 MBq [123I]diiodotyrosyl22-SCT, containing less than 4 IU hormone, imaged dynamically up to 0.5 h and at intervals up to 24 h) shows early uptake in liver, kidney and sites of known Paget's disease but not in normal bone, and later uptake in thyroid and stomach. Blood clearance was fitted to a biexponential with half-lives of 3.4-7.4 min and 3-34 h. Radiation dosimetry was estimated using MIRDOSE 3. The highest doses (mean mGy/MBq) were to thyroid (6.8x10(-1)) and kidney (6.0x10(-2)), with a whole-body dose 3.0x10(-2). High performance liquid chromatography analysis revealed that urinary radioactivity was mostly in the form of iodide and diiodotyrosine within minutes of injection, indicating rapid in vivo breakdown. In summary, [123I]diiodotyrosyl22-SCT binds to calcitonin receptors and can image sites of Paget's disease but its imaging potential is not optimal because of rapid breakdown and clearance from target tissues, and an alternative radiolabelling approach is required.

Aged↗

Metabolism of 15-(4'-[123I]iodophenyl)pentadecanoic acid ([123I]IPPA) in the rat heart; identification of new metabolites by high pressure liquid chromatography and fast atom bombardment-mass spectrometry.

The metabolism of 15-(4'-iodophenyl)pentadecanoic acid (IPPA) in the heart muscle is commonly believed to end at 4-iodobenzoic acid as the main and final product of beta-oxidation. However, investigation of the metabolic fate of IPPA in Langendorff rat hearts using high pressure liquid chromatography (HPLC) and negative fast atom bombardment mass spectrometry (FAB-MS) revealed new results. After perfusing isolated rat hearts with [123I]IPPA, metabolites were monitored by HPLC using simultaneous detection of gamma-radioactivity and u.v. absorbance. The identification of HPLC separated metabolites was based on their nominal molecular weights as determined by negative FAB-MS. According to these measurements five catabolites were identified with decreasing concentration: 3-(4'-iodophenyl)propanoic acid >> 3-(4'-iodophenyl)propanoic acid = 5-(4'-iodophenyl)-3-hydroxypentanoic acid >> 4-iodobenzoic acid. Additionally, an anabolic metabolite was found exclusively in the lipid ester fraction. From the hydrolysed heart lipids this compound was identified as 11-(4'-iodophenyl)undecanoic acid. Its formation is explained by the action of cytosolic fatty acid synthetase on IPPA catabolites. This metabolic behaviour may be of importance for the interpretation of sequential heart scintigraphy performed with [123I]IPPA.

Animals↗

Synthesis and preliminary evaluation of [123I]1-(4-cyanobenzyl)-4-[[(trans-iodopropen-2-yl)oxy]meth yl]piperidin e: a novel high affinity sigma receptor radioligand for SPECT.

1-(4-Cyanobenzyl)-4-[[(trans-iodopropen-2-yl)oxy]methyl]pipe ridine (2) has been synthesized as a novel iodinated ligand for sigma receptors. This new compound exhibited high affinity (Ki = 0.38 nM) for the sigma-1 receptor and selectivity for sigma-1 vs. sigma-2 receptors (Ki sigma-1/sigma-2 = 0.02) using in vitro receptor binding assays. Moderate affinity for muscarinic M1 (Ki = 322 nM) and M2 (Ki = 178 nM) receptors and low affinity (Ki = 1,460 nM) for dopamine D2 receptors was also noted. The lipophilicity of 2 (log P7.5 = 3.24) is moderate, indicating that the ligand should readily cross the blood/brain barrier. The corresponding radioiodinated ligand, 123I-2, was synthesized from the appropriate trans vinyl tributylstannane precursor under acidic conditions using oxidative iododestannylation methods. HPLC purification provided the radioligand in yields ranging between 63 and 75% EOS (n = 5) and with > 99% radiochemical purity and a specific activity > 77,000 MBq/mumol. Preliminary in vivo distribution and pharmacological blocking studies using 123I-2 were performed in male Australian Albino Wistar rats. 123I-2 exhibited good brain uptake (1.11 +/- 0.14% ID at 20 min PI) with no significant loss of radioactivity from the brain over the course of the study (4 h). The gross regional brain distribution of the radioligand showed highest uptake in the posterior cortex and frontal cortex, with slightly lower uptake in other brain regions examined. Most of the uptake of radioactivity in the brain, lung, heart, muscle, and kidney was prevented by pre-administration of compounds with affinity for sigma receptors, indicating the in vivo specificity of the ligand. In view of these results, 123I-2 shows promise for the in vivo tomographic evaluation of sigma receptor densities.

Animals↗

[Thyroxine deiodination in the fetus].

T4 deiodination has been studied using the fetal liver and kidney of miniature goats during late pregnancy. They were homogenized in 0.15M phosphate buffer, pH7.4 to make 25% homogenate which was incubated with outer ring labeled 125I-T4, 125I-rT3 or inner ring labeled 125I-T4 at 37 degrees C for 15, 30, 60, 90 or 120 min. either with or without 20mM DTT. After incubation they were extracted in ethanol and subjected to TLC to separate 125I-compounds. The radioactivity of each compound was measured and its production rate was expressed as a percentage of total radioactivity of the extract. The activity of deiodination in the outer ring of T4 in fetal liver was similar to that observed in the mother's . Fetal kidney showed a markedly increased activity in deiodination in the inner ring compared to that of all the other tissues studied. In contrast it showed the lowest deiodination in the outer ring. The addition of 20mM DTT had little effect on T4 deiodination in fetal organs. These data indicate a significant difference between T4 deiodinating activity in the liver and kidney of the fetus. It is felt that the kidney plays a more important role in T4 deiodination than the liver during fetal life.

Animals↗

Quantitative immunoautoradiography at the cellular level. II. Absolute measurements using labeled standard cells as a source of reference.

A quantitative autoradiographic method is presented for determining absolute amounts of 125I-labeled compounds on the surface of individual cells. Autoradiographic evaluation of single cell radioactivity is accomplished by comparing the silver grain densities over the specimen and a radioactive standard being exposed simultaneously. In order to obtain a reference source of comparable physical properties, surface-radioiodinated human erythrocytes are used, the radioactivity of which is determined in a crystal counter. A simple enzymatic method for preparing such standard erythrocytes of very uniform label density is described. Numerous experimental advantages derived from the use of the standard are discussed and demonstrated by examples employing various exposure times and different radioactive standards. Hereby, very similar results were obtained when the number of A-antigenic sites was quantified on single erythrocytes in different experiments. The quantification of membrane-bound IgM on single human lymphocytes is shown as another application of this scheme.

Autoradiography↗

75,77Br- and 123I-analogues of D-glucose as potential tracers for glucose utilisation in heart and brain.

A number of D-glucose analogues labelled with either the positron emitter 75Br (T 1/2 = 1.6 h) or the single photon emitter 123I (T 1/2 = 13.3 h) were studied as potential tracers for glucose utilisation in heart and brain. Of these, 3-deoxy-3-bromo-D-glucose, 3-deoxy-3-iodo-D-glucose, methyl 2-deoxy-2-bromo-beta-D-glucoside and methyl 2-deoxy-2-iodo-beta-D-glucoside showed little uptake of radioactivity into brain and an unfavourable ratio of heart-to-blood and heart-to-lung concentrations. In contrast, methyl 3,4,6-tri-O-acetyl-2-deoxy-2-iodo-beta-D-glucoside (MTIG) and methyl 3,4,6-tri-O-acetyl-2-deoxy-2-bromo-beta-D-glucoside (MTBG) showed promising brain uptake (160% MBC for MTBG) with a good brain-to-blood concentration ratio of 0.8. MTBG is not metabolically altered in the brain. Thus, this compound may be a promising tracer for measuring glucose transport if it proves to be a substrate for the hexose carrier at the blood-brain-barrier.

Animals↗

The bidirectional transfer and fetal vascular pressure changes due to the presence of 125I-labeled inhibin A in the ex-vivo human placental model.

OBJECTIVE: The purpose of this study was to investigate the transport of inhibin A and to determine its effects on fetal vascular pressure at elevated levels in the human placenta using 125I-labeled synthetic glycoprotein. METHODS: Synthetic inhibin A was prepared and was shown to be consistent with the natural form by high-pressure liquid chromatography (HPLC) and molecular weight determination by gas-chromatography mass spectrometry. The standardized Na125I process yielded 125I-labeled inhibin A with a radioactivity of 10(6) cpm/microg. This compound was placed in the human placenta in maternal-fetal and fetal-maternal studies using antipyrine and 14C-labeled inulin as controls to determine the bidirectional transfer of the compound. RESULTS: Maternal-fetal and fetal-maternal clearance indices were 0.045 +/- 0.003 and 0, respectively. In eight placentas there was no evidence of vascular pressure changes due to the presence of up to 5000 pg of inhibin A. CONCLUSIONS: There is minimal maternal-fetal transfer and no detectable fetal-maternal transfer in normotensive and pregnancy-induced hypertensive placentas. In addition, there are no pressure changes in the fetal vascular system due to the clinically significant levels of inhibin A.

Chromatography, High Pressure Liquid↗

Bioavailability of 125I bromelain after oral administration to rats.

Bromelain is a sulphydral protease, derived from the stem and fruit of pineapples. Semi-purified preparations of bromelain are used in the treatment of inflammation and oedema. There is however no unequivocal proof of the absorption of the enzyme after oral administration. In this study, 125I-bromelain was administered orally to rats and blood sampled at various times. The total radioactivity, the TCA precipitable 125I-compounds and the molecular weight profile of 125I-proteins in the plasma were determined. A maximum level, equivalent to 270 ng ml-1 bromelain was found at 1 h after administration. Approximately 40 per cent of the 125I in plasma could be precipitated by 10 per cent trichloroacetic acid. Electrophoretic analysis showed one major peak of radioactivity in the plasma samples, with a molecular weight of 26-32,000 daltons. This is identical to the main molecular weight fraction in the Bromelain mixture and corresponds to the molecular weight of the purified enzyme. In the 1 h plasma sample this peak contained 0.003 per cent of the administered dose per millilitre.

Administration, Oral↗

Current status of radioimmunodetection.

Radioimmunodetection is a nuclear medicine technique that depends on in vivo detection of localization of antibodies and antibody forms carrying radioactivity for the purpose of diagnosis in patients with cancer. Current methods take advantage of tracers suitable for high resolution gamma-camera imaging, such as 99mTc and 111In, for common tumors, such as colon and lung cancers. In addition, tracers such as 125I have been used for the intraoperative detection of metastatic deposits. These methods detect from 75 to 90% of metastatic deposits with high specificity, and typically contribute important diagnostic information, even in 25-40% of patients with occult disease.

Clinical Trials as Topic↗

Radiolabelled peanut lectin for the scintigraphic detection of cancer.

To investigate the role of intravenously administered, radioiodinated peanut lectin (131I-PNA) in the non-invasive detection of cancer, the pharmacokinetics and scintigraphic distribution of this novel tumor-seeking compound were studied in 8 patients with metastatic cancer of the colon, breast or lung. Scintigraphic localization of 131I-PNA was apparent at certain anatomical sites of known metastases in 2 patients and in a further 2 patients an adjacent malignant pleural effusion was visualized. The rapid clearance of radioactivity from the whole body and plasma with marked renal concentration and rapid urinary excretion of significant amounts of intact 131I-PNA (mol. wt. 107,000, pI 5.95) implied that this molecule was excreted selectively by the renal tubules. PNA or other lectins may find a role in the scintigraphic detection of selected types of cancer.

Arachis↗

Technetium-fibrinogen lung scanning in canine lung contusion.

To detect experimentally induced acute lung contusion in anesthetized dogs, serial radionuclide images of the lung were recorded following intravenous infusion of 99mTc-labelled human fibrinogen (Tc-HF). The accumulation of Tc-HF in canine lungs was serially quantitated for up to 20 hours after lung contusion. A contusion (#1) was produced in one lung, Tc-HF was injected IV after 15 minutes, and 75 minutes later a contralateral lung contusion (#2) was produced in a series of 14 dogs. At autopsy the excised lungs were scanned, sectioned, and counted for radioactivity. Radiolabelled fibrinogen accumulated within 2-4 minutes of contusion #2 and remained stable over the next 20 hours in 14 dogs; contusion #1 was barely visible in four dogs. Lung Tc-HF activity in the central region of contusion #2 remained sixfold higher than in normal lung tissue. These data suggest that following lung contusion, fibrinogen deposition occurs rapidly and remains stable over a 20-hour interval of observation.

Animals↗

Site-specific conjugation of a radioiodinated phenethylamine derivative to a monoclonal antibody results in increased radioactivity localization in tumor.

The preparation of a novel radioiodination reagent, the (aminooxy)acetyl derivative of (p-[125]-iodophenyl)ethylamine, is described. Conventional radioiodination of proteins involves the formation of iodotyrosine residues, but for in vivo applications such as thyroid or stomach immunoscintigraphy, the susceptibility of these residues to tissue dehalogenases constitutes a serious disadvantage. Using our new compound, which has a particularly nonreactive aromatic ring, we confirm and extend studies published by other workers indicating the much greater in vivo stability of iodophenyl compounds compared to the more conventional iodophenolic ones. In addition, the aminooxy group of our reagent gives a stable and specific linkage to aldehyde groups formed by periodate oxidation on the sugar moiety of antibody molecules. In vitro, favorable binding activity and high stability was obtained with a (([125I]iodoaryl)amino)oxy labeled monoclonal antibody directed against carcinoembryonic antigen. In vivo, using paired labeling experiments in nude mice bearing colon carcinoma xenografts, the (([125I]iodoaryl)amino)oxy-MAb (MAb = monoclonal antibody) was compared with the same MAb 131I-labeled by conventional chloramine-T method. Tumor 125I concentration of (arylamino)oxy MAb (measured as percent injected dose per gram) was significantly higher as compared to values obtained with a conventionally labeled 131I antibody. Additionally, thyroid uptake, an indicator of iodine release from the antibody, was up to 25 times lower after injection of 125I-MAb obtained by the new method as compared to the conventionally iodinated 131I-MAb.

Animals↗