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Background: Therapeutic drug monitoring (TDM) and dose adjustment of lenvatinib may be beneficial in the treatment of radioiodine-refractory thyroid cancer, by maximizing antitumor effects and minimizing adverse drug reactions. The aim of this study was, therefore, to develop and validate a high-performance liquid chromatography method using an ultraviolet detection system for routine serum lenvatinib detection in patients with thyroid cancer., Methods: Serum specimens, spiked with an internal standard, were treated by a solid-phase extraction through an octadecylsilyl silica cartridge. Lenvatinib and internal standard were concomitantly separated from serum using a conventional octadecylsilyl silica column through isocratic elution, using a mobile phase consisting of 0.02 mol/L sodium phosphate (pH 6.7) and acetonitrile (50/50, vol/vol) at a flow rate of 1.0 mL/min. The detection wavelength was set at 244 nm. Serum samples from 5 patients were used for clinical validation of the method., Results: The calibration curve for lenvatinib was linear (Pearson correlation coefficient, r = 0.9998) over the concentration range of 6.25-400 ng/mL, with a lower limit of quantification of 6.25 ng/mL. Extraction recoveries for lenvatinib were 97% or more, with coefficients of variation less than 2.2%. The coefficients of variation for intraday and interday assays were less than 4.7% and 6.0%, respectively., Conclusions: This sensitive high-performance liquid chromatography method can be used for lenvatinib therapeutic drug monitoring when liquid chromatography-tandem mass spectrometry facilities are unavailable.

Objectives: In vivo evaluations of a gonadotropin releasing hormone-receptor single photon emission computed tomography radiotracer for non-invasive detection of gonadotropin releasing homone-receptors in brain., Results: We have used a simple, robust and high-yielding procedure to radiolabel an alpha-halogenated bioactive compound with high radiochemical yield. Literature findings showed similar alpha-halogenated compounds suitable for in vivo evaluations. The compound was found to possess nano molar affinity for the gonadotropin releasing hormone-receptor in a competition dependent inhibition study. Furthermore, liquid chromatography-mass spectrometry analysis in saline, human and rat serum resulted in 46%, 52% and 44% stability after incubation for 1 h respectively. In addition, rat brain single photon emission computed tomography and biodistribution studies gave further insight into the nature of the compound as a radiotracer.

Purpose: To propose a new and effective dose regimen for stable potassium iodide (KI) repeated prophylaxis in case of prolonged exposure to radioactive iodine., Methods: The pharmacokinetics of iodine was determined in rats by compartmental analyses after intravenous and oral administrations of the optimal dose of 1 mg/kg KI, which was previously selected in a dose-effect study. The thyroid protection against iodine-125 incorporation was followed during 24 h after a single oral dosing of KI. A repeated KI prophylaxis was modeled using initial estimates of iodine pharmacokinetic parameters., Results: A dose regimen consisting in administrations of 1 mg/kg daily for 8 days was selected and studied. Plasma iodine concentrations predicted by simulation were verified by experimental data and varied after the third dose of KI between 174 and 1190 μg/l. The inhibition study of iodine-125 binding in the thyroid as a function of the time showed that the protection effect of KI could be correlated to stable iodine plasma concentrations. Hence, a theoretical decrease in iodine-125 thyroid uptake from 63 to 88% could be achieved in a 24 h-interval between two KI doses., Conclusion: Given the satisfactory levels of thyroid protection, this dose regimen could be envisaged in order to extent KI indications for repeated prophylaxis.

Challenges facing cardiovascular imaging necessitate innovation of better radiopharmaceuticals to augment or replace the existing ones. This research assesses the ability and competency of radioiodinated esmolol as a potential cardio selective imaging agent. Radioiodinated esmolol was synthesized with 97.3 ± 0.3% radiochemical yield and with high stability up to 48 h at room temperature as well as in rat serum. Molecular modeling study was performed to confirm the binding of iodinated esmolol to β 1 -adrenergic receptor. Its biodistribution studies in normal Swiss albino mice showed high heart uptake (38.5 ± 0.11%ID/g at 5 min p.i.), heart/liver ratio nearly 3.85:1 and heart/lungs ratio was about 7:1 at 5 min p.i. The evidenced selectivity of the radioiodinated esmolol to β 1 -adrenoceptor was confirmed by prior injection of cold esmolol. Gamma camera biodistribution pattern showed that radioiodinated esmolol accumulated selectively in heart., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Aim: The aim of this study was to assess the agreement between predicted blood uptake values using I and actually measured I blood uptake values (reference) in patients with differentiated thyroid carcinoma receiving largely high therapeutic activities., Patients and Methods: Fourteen patients were analyzed retrospectively, who underwent a series of both pretherapeutic and intratherapeutic blood sampling using median I activities of 23 MBq and median therapy I activities of 10 GBq. Data of five blood samples from each patient were analyzed. Lin's concordance correlation coefficient analysis was carried out to assess the kinetic agreement. The time-integrated I activity coefficient (TIAC) for the blood compartment and the effective I clearance time (ECT), expressed as effective I half-life on the basis of a monoexponential model, were ascertained. For each patient, the (intrapatient) percentage differences between pretherapeutic and intratherapeutic TIACs and ECTs were calculated. The (interpatient) difference in TIACs and ECTs between pretherapy and intratherapy groups was evaluated using the Mann-Whitney U-test., Results: Lin's concordance correlation coefficient was at least 0.97, indicating substantial kinetic agreement between pretherapeutic and intratherapeutic radioiodine kinetics. The mean (median)±SD (range) of the absolute percentage difference was 9% (11%)±7% (0.33-20%) for the TIAC and 11% (10%)±10% (0-23%) for the ECT. A slightly higher median TIAC was observed in intratherapy (2.8 vs. 3.3 h), but this was not statistically significant (P=0.15), whereas no remarkable ECT difference (P=0.62) was found., Conclusion: The pretherapeutic blood kinetics derived from diagnostic I activities provides a reliable estimation of the intratherapeutic I blood kinetics in patients receiving largely high therapy activities, showing its potential for radioiodine treatment planning.

Biodistribution of [ 125 I]Aimpila (20 mg/kg) in the tumor and normal tissues, including the mammary gland tissue, after single oral dose was studied in BALB/c nude mice with T47D/ReCAF +++ human breast tumor sensitive to this drug and in closely related BALB/c nude + mice without tumors. The maximum concentration of [ 125 I]Aimpila was in fact the same in the tumor and in the mammary gland, while the time course of its accumulation/elimination differed. The time of the maximum accumulation of the drug in the tumor was shorter and its persistence longer than in normal tissue. After 24 h, label concentration in the tumor was 4.5 times higher (p=0.002). Differences in the time course of label accumulation in the tumor were detected. The maximum ratio of tumor/blood concentrations of the preparation was recorded in 1 h after administration. [ 125 I]Aimpila and [ 125 I]alpha-fetoprotein accumulated in the tumor in comparable concentrations and were eliminated simultaneously at the same rate. The results of comparative analysis of accumulation of the labeled compounds in Aimpila-sensitive T47D/RECAF +++ tumor from 0.5 to 9.0 h after drug administration could be interpreted as a result of possible receptor-mediated binding of the complex with the tumor at the expense of the alpha-fetoprotein transporting part. Differences in the parameters of [ 125 I]Aimpila biodistribution in the tumor and normal mammary tissue indirectly attested to selective antiproliferative activity of the complex.

Clinical trials showed renal protective effects of bovine intestinal alkaline phosphatase (AP) in patients with sepsis-associated acute kidney injury (AKI). Subsequently, a human recombinant chimeric AP (recAP) was developed as a pharmaceutically acceptable alternative. Here, we investigated the biodistribution and pharmacokinetics (PK) of recAP and developed a translational population PK model. Biodistribution was studied during LPS-induced AKI in rats. Iodine-125-labeled recAP was primarily taken up by liver, spleen, adrenals, heart, lungs and kidneys followed by the gastro-intestinal tract and thyroid. Tissue distribution was not critically affected by endotoxemia. PK parameters were determined in rats and minipigs during IV bolus injections of recAP, administered once, or once daily during seven consecutive days. Plasma concentrations of recAP increased with increasing dose and disappeared in a biphasic manner. Exposure to recAP, estimated by AUC and Cmax, was similar on days 1 and 7. Subsequently, population approach nonlinear mixed effects modeling was performed with recAP rat and minipig and biAP phase I PK data. Concentration versus time data was accurately described in all species by a two-compartmental model with allometric scaling based on body weight. This model provides a solid foundation for determining the optimal dose and duration of first-in-man recAP studies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Excess body fat or obesity is known to increase risk of poor vitamin D status in nonathletes but it is not known if this is the case in athletes. Furthermore, the reason for this association is not understood, but is thought to be due to either sequestration of the fat-soluble vitamin within adipose tissue or the effect of volume dilution related to obese individuals' larger body size. Forty two US college athletes (24 men 18 women, 20.7 ± 1.6 years, 85.0 ± 28.7 kg, BMI = 25.7 ± 6.1 kg/m2) provided blood samples during the fall and underwent measurement of body composition via dual energy X-ray absorptiometry. Serum samples were evaluated for 25-hydroxyvitamin D (25(OH)D) concentration to assess vitamin D status using Diasorin 25(OH)D radioiodine assay. Serum 25(OH)D concentration was negatively associated with height (r = -0.45), total body mass (r = -0.57), BMI (r = -0.57), body fat percentage (r = -0.45), fat mass (r = -0.60) and fat-free mass (r = -0.51) (p < .05). These associations did not change after controlling for sex. In a linear regression mixed model, fat mass (coefficient -0.47, p = .01), but not fat-free mass (coefficient -0.18, p = .32) significantly predicted vitamin D status and explained approximately 36% of the variation in serum 25(OH)D concentration. These results suggest that athletes with a large body size and/or excess adiposity may be at higher risk for vitamin D insufficiency and deficiency. In addition, the significant association between serum 25(OH)D concentration and fat mass in the mixed model, which remained after controlling for sex, is in support of vitamin D sequestration rather than volume dilution as an explanation for such association.

The amount of 131I necessary for successful ablation in patients with differentiated thyroid cancer (DTC) is still subject to debate. This study investigates the relationship of the absorbed dose of radiation to the blood while administering 131I activity with several other parameters in DTC patients. This prospective study included 90 DTC patients who were classified into three groups according to their level of dosage: 3.7 GBq (38.9%), 5.55 GBq (55.6%), and 7.4 GBq (5.5%). Blood dosimetry of treated patients was performed using external whole-body counting with a Geiger Muller dosimeter located 2 m away from the patients. Dose rate was measured at 2, 4, 5, 24, and 48 h after the administration of radioiodine. Based on the results of whole-body dose rate measurements, 48 h after administration of 3.7, 5.55, and 7.4 GBq of radioiodine, absorbed doses to patients' blood were estimated at 0.49 ± 0.12, 0.71 ± 0.21, and 0.76 ± 0.11 Gy, respectively. Increasing radioiodine dosage from 3.7 GBq to 5.55 GBq significantly increased blood dose, while there was no significant difference in blood dose between radioiodine dosages of 5.55 GBq and 7.4 GBq. The absorbed dose to the blood was significantly correlated to the patients' gender and the presence of lymph node metastases, but it was not significantly correlated to the type of pathology and regional or distant metastases. Ablation activities exceeding 5.55 GBq produce no further increase in the accumulated activity per volume of blood. The literature regarding this issue is scarce, and further studies are required to verify these preliminary results.

In this study, the regional rat brain distribution of radioiodinated o-iodo-trans-decalinvesamicol ([(125) I]OIDV) was determined in vivo to evaluate its potential as a single-photon emission computed tomography (SPECT) imaging probe for vesicular acetylcholine transporter (VAChT). Following intravenous injection, [(125) I]OIDV passed freely across the blood-brain barrier and accumulated in rat brain. The accumulation of [(125) I]OIDV in rat brain was significantly reduced by coadministration of (+/-)-vesamicol (0.125 µmol). In contrast, the coadministration of σ-receptor ligands, such as (+)-pentazocine (0.125 µmol) as a σ-1 receptor ligand and (+)-3-(3-hydroxyphenyl)-N-propylpiperidine (0.125 µmol) as a σ-1 and σ-2 receptor ligands, barely affected the accumulation of [(125) I]OIDV in rat brain. These findings in vivo were corroborated by autoradiographic analysis ex vivo. The authors found that the tracer binds with pharmacological selectivity to VAChT in rat brain and predicted that it may likewise serve in translational SPECT imaging studies of this marker in the integrity of cholinergic innervations., (Copyright © 2013 Wiley Periodicals, Inc.)

Based on animal model studies, [131I]IAZA may be useful as an adjunct radiotherapeutic (MRT) drug for the treatment of tumor hypoxia. However, radioactivity in the blood of patients and healthy volunteers dosed with [123I]IAZA has a protracted terminal elimination phase in which clearance is influenced by free [123I]IAZA and possibly by unidentified metabolites. The current work reports that about 40% of the radioactivity in human serum is associated with the serum protein fraction, and that the free:bound ratio is constant at about 60:40 for at least the first 135 min after injection, as determined by radio-HPLC analyses. In order to modulate the clearance of bound and free radioactive IAZA, nonradioactive (cold) IAZA was administered i.v. 1 h following injection of high specific activity [125I][IAZA in the Balb/C EMT-6 murine tumor model. This 'wash out' procedure reduced the concentrations of radioactivity by at least 40% in all tissues, with greatest effect in kidney and liver, and least in tumor. As a result, the tumor:blood ratio increased from 5.8 to 8.5 at 4 h post-injection. This effect would be advantageous for the use of [131I]IAZA as an MRT drug. Optimization of intervals between radioactive and wash out dose, and confirmation of the self-irradiation dose to all tissues, remain to be undertaken before [131I]IAZA can be tested as a low-dose-rate MRT supplement to external beam x-ray radiotherapy.

Radioactive iodide ((131)I-) protection studies have focused primarily on the thyroid gland and disturbances in the hypothalamic-pituitary-thyroid axis. The objective of the current study was to establish (131)I- urinary excretion profiles for saline, and the thyroid protectants, potassium iodide (KI) and ammonium perchlorate over a 75 hour time-course. Rats were administered (131)I- and 3 hours later dosed with either saline, 30 mg/kg of NH(4)ClO(4) or 30 mg/kg of KI. Urinalysis of the first 36 hours of the time-course revealed that NH(4)ClO(4) treated animals excreted significantly more (131)I- compared with KI and saline treatments. A second study followed the same protocol, but thyroxine (T(4)) was administered daily over a 3 day period. During the first 6-12 hour after (131)I- dosing, rats administered NH(4)ClO(4) excreted significantly more (131)I- than the other treatment groups. T(4) treatment resulted in increased retention of radioiodide in the thyroid gland 75 hour after (131)I- administration. We speculate that the T(4) treatment related reduction in serum TSH caused a decrease synthesis and secretion of thyroid hormones resulting in greater residual radioiodide in the thyroid gland. Our findings suggest that ammonium perchlorate treatment accelerates the elimination rate of radioiodide within the first 24 to 36 hours and thus may be more effective at reducing harmful exposure to (131)I- compared to KI treatment for repeated dosing situations. Repeated dosing studies are needed to compare the effectiveness of these treatments to reduce the radioactive iodide burden of the thyroid gland.

Several dosimetric methods have been proposed for estimating red marrow absorbed dose (RMAD) when radionuclide therapy is planned for differentiated thyroid cancer, although to date, there is no consensus as to whether dose calculation should be based on blood-activity concentration or not. Our purpose was to compare RMADs derived from methods that require collecting patients' blood samples versus those involving OLINDA/EXM software, thereby precluding this invasive procedure. This is a retrospective study that included 34 patients under treatment for metastatic thyroid disease. A deviation of <10 % between RMADs was found, when comparing the doses from the most usual invasive dosimetric methods and those from OLINDA/EXM. No statistical difference between the methods was discovered, whereby the need for invasive procedures when calculating the dose is questioned. The use of OLINDA/EXM in clinical routine could possibly diminish data collection, thus giving rise to a simultaneous reduction in time and clinical costs, besides avoiding any kind of discomfort on the part of the patients involved.

The objective of this study was to explore the inter-relationship of three platelet measures of serotonergic function (5-HT): 5-HT Transporter Binding, 5-HT-2 Receptor Binding and 5-HT Content and to explore their inter-relationship with measures of aggression and impulsivity. 58 male subjects with personality disorder were studied. Numbers of platelet 5-HT Transporter and 5-HT-2 Receptor sites were assessed by examining the Bmax of ³H-Paroxetine Binding and the Bmax of ¹²⁵I-LSD Binding to the blood platelet; 5-HT Content was assessed by measuring the amount of 5-HT in the platelet material. Life history of aggression was assessed by Life History of Aggression. Impulsivity was assessed by the Impulsivity Scale of the Eysenck Personality Questionnaire-II. Platelet 5-HT Transporter Binding correlated with both 5-HT-2 Receptor Binding and 5-HT Content; the latter two variables did not correlate with each other. Only Platelet 5-HT Transporter binding correlated significantly with LHA Aggression. These data suggest that while Platelet 5-HT Transporter binding correlates with both 5-HT-2 Receptor Binding and with 5-HT Content, that only 5-HT Transporter Binding represents a correlate of aggression in male personality disordered subjects., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: A new promising approach to improve the outcome of head and neck squamous cell carcinoma (HNSCC) is the application of radio-labeled antibodies directed against tumor-associated antigens. Cytokeratin 8 (CK8), an intermediate filament forming protein, is shown to be de novo expressed in dysplastic lesions as well as in HNSCC. Therefore like the epithelial cell adhesion molecule CK8 seems to be a suitable anchor molecule for targeted radioimmunotherapy (RIT). The aim of this study was to investigate the biodistribution of a radio-labeled Cytokeratin 8-specific monoclonal antibody (mAb) in a SCID (severe combined immunodeficiency disease) mouse model., Materials and Methods: The mAb against CK8 was labeled with (131)I and biodistribution was tested in established HNSCC xenografts in SCID mice. The biodistribution of the mAb in the tumor and different organs was determined with a gamma counter and was calculated as % injected dose/gram tissue., Results: Initially, after systemic administration of (131)I-anti CK8 monoclonal antibody high activity was seen in all the organs. Over time the general activity decreased, whereas activity accumulated in the tumor. This activity decayed compared to the other tissues with a two- to threefold prolonged radioactive half-life., Conclusion: Specific antibody-antigen-binding is probably responsible for the prolonged radioactive half-life in the tumor and the resulting cumulative activity due to enrichment of the (131)I-anti CK8 mAb, so that Cytokeratin 8 seems to be a suitable anchor molecule for radioimmunotherapy in HNSCC.

Background: Occasionally, blood samples may be required from thyroid cancer patients after they have been given the therapy dose of (131)I, as part of necessary medical management of comorbidities. Thus, in the days after (131)I administration, medical health professionals may be involved in the withdrawal, handling, and manipulation of radioactive blood samples. The purpose of this study was to quantify the amount of radioactivity in blood samples taken from thyroidectomized thyroid carcinoma patients after the administration of therapeutic activities of (131)I., Methods: For dosimetry purposes, serial blood sampling is performed on thyroidectomized thyroid carcinoma patients prior to therapy with (131)I. The quantities of radioactive material present in these blood samples were expressed as a percentage of the administered activity and then extrapolated to the high levels of (131)I used in therapy for 377 patients in this study. The corresponding radiation exposure rate from the blood samples was then calculated to determine what radiation protection methods were required for staff handling these samples., Results: The average amount of radioactivity in a 1 mL blood sample at 1 hour postadministration of 5.5 GBq (150 mCi) of (131)I was 0.2 ± 0.15 MBq (5.4 ± 4.0 μCi). This corresponds to an exposure rate of 1.23 μSv/h (0.123 mrem/h) at 10 cm from the sample. For samples obtained beyond 24 hours after a therapeutic administration of 5.55 GBq (150 mCi), the exposure levels are approximately equal to background radiation., Conclusion: The data in this study indicate that the radiation exposure from blood samples withdrawn from thyroidectomized thyroid cancer patients is low. However, to ensure that staff members are exposed to minimal levels of radiation, it is imperative that staff members who are involved in withdrawing, handling, or manipulating radioactive blood samples adhere to the recommended radiation safety practices.

Thyroid status was assessed in adult female rhesus monkey breeders at the California National Primate Research Center at the beginning of the breeding season. The 95% confidence intervals for thyrotropin (TSH), thyroxine (T(4)) and triiodothyronine (T(3)) (n = 66-80) were similar to those previously reported in smaller samples of macaque monkeys. Based on human criteria, 10 of 80 monkeys (12%) were hypothyroid (TSH > 2.0 µIU/mL). Because hypothyroxinaemia can be a risk factor in pregnancy, T(4) status was compared with past breeding history, breeding outcome for that season and general health records in a subset of 42 breeders. Age, weight and parity did not differ between monkeys in the lowest T(4) quartile as compared with those in the upper three quartiles. However, T(4) concentrations were significantly associated with the number of missed menstrual cycles during the previous breeding season. In additional work, three healthy lactating rhesus monkeys were given three different doses of environmental contaminant and thyroid iodine uptake inhibitor, ammonium perchlorate (0.006, 0.34, 12.8 mg/kg/day, respectively) in food for two weeks. Thyroid status variables (TSH, T(4), T(3), thyroid radioactive iodine uptake) were then measured. In the monkey receiving the highest perchlorate dose, iodine uptake was suppressed relative to baseline. The study shows the availability of tools to study thyroid status in rhesus monkeys, the variability of thyroid status in the breeder colony and the potential ability of environmental factors to influence thyroid status.

We present data on repeated iodine-131 whole body scans ((131)I-WBS) in differentiated thyroid cancer patients (DTC) after surgery and (131)I remnant ablation and on increased thyroglobulin (Tg) with negative (131)I-WBS, in a retrospective study at our hospital. A total of 106 patients (91 female and 15 male) treated with (131)I for DTC met the inclusion criteria. The mean age of the patients was 45 years, age range 16-81 years. A total of 101 patients had complete 24 months follow-up following (131)I remnant ablation treatment. The mean (131)I dose administered after the first 6 months of follow- up was 3GBq while mean total dose was 4.9GBq, range 1.1-7.4GBq. Our results showed that at the end of the first 6 months post treatment, 58/101 patients had a negative (131)I-WBS. By the end of the 4th (131)I treatment at 24th months, the remaining 43 patients became negative for (131)I-WBS. We found increased Tg and negative (131)I-WBS in 2 of the 101 patients at the 24th months examination the so called Tg elevated negative (131)I-WBS (TENIS syndrome). The possible explanation of this syndrome is discussed. In conclusion, our study in DTC operated patients does not support the use of repeated diagnostic (131)I-WBS after an undetectable Tg because we found no Tg rebound in patients with negative (131)I-WBS, after 24 months of follow-up with serial measurements of Tg on and of suppression with L thyroxine.

The standard treatment for the ablation of thyroid remnant tissue following surgery as well as for the treatment of iodine avid metastases in patients suffering from differentiated thyroid cancer (DTC) is therapy with radioactive iodine. Mostly fixed standard activities are used with the inherent risk of under- or overdosing the patient. Therefore, the rationale for using a dosimetry-based approach is to replace the conventional fixed activity regimen by a patient-tailored approach which allows the administered therapeutic activity to be increased while avoiding unwanted side effects. The purpose of this review was to describe the presently used dosimetric concepts: 1) the blood dosimetry approach (optimizing the "safety" aspect of the treatment); and 2) lesion-based dosimetry (optimizing the "efficacy" of the treatment) and their respective clinical findings. In addition, a simplified method for performing blood dosimetry and its application towards further enhancement of radioiodine therapies are introduced. Finally, a new concept for potentially determining patient-specific radiation sensitivity using blood dosimetry is introduced.

Purpose: The residence time of (131)I in the blood is likely to be a measure of the amount of (131)I that is available for uptake by thyroid remnant tissue and thus the radiation absorbed dose to the target tissue in (131)I ablation of patients with differentiated thyroid cancer (DTC). This hypothesis was tested in an investigation on the dependence of the success rate of radioiodine remnant ablation on the radiation absorbed dose to the blood (BD) as a surrogate for the amount of (131)I available for iodine-avid tissue uptake., Methods: This retrospective study included 449 DTC patients who received post-operative (131)I ablation in our centre in the period from 1993 to 2007 and who returned to us for diagnostic whole-body scintigraphy. The BD was calculated based on external dose rate measurements using gamma probes positioned in the ceiling. Success of ablation was defined as a negative diagnostic (131)I whole-body scan and undetectable thyroglobulin levels at 6 months follow-up., Results: Ablation was successful in 56.6% of the patients. The rate of successful ablation correlated significantly with BD but not with the administered activity. Patients with blood doses exceeding 350 mGy (n = 144) had a significantly higher probability for successful ablation (63.9%) than the others (n = 305, ablation rate 53.1%, p = 0.03). In contrast, no significant dependence of the ablation rate on the administered activity was observed., Conclusion: The BD is a more powerful predictor of ablation success than the administered activity.

To investigate the changes of regional cerebral blood flow (rCBF) in early-onset anorexia nervosa (AN) before and after weight gain, we examined resting rCBF using single photon emission computed tomography (SPECT) with [(123)I]iodoamphetamine ((123)I-IMP). Ten female children with AN (mean age 13.2 years old) participated in this study. SPECT examinations were performed in all patients twice at the beginning of treatment and after weight gain. The mean body mass index (BMI) was changed from 13.1 to 16.6 during 4 months treatment period. Automatic voxel-based analysis of the images was carried out using statistical parametric mapping (SPM) software. Relatively increased rCBF in the bilateral parietal lobe and limbic lobe including the posterior cingulate cortex (PCC) were observed after weight gain in early-onset AN. There was no significant decrease in the rCBF after weight gain. A significant positive correlation was observed between BMI and rCBF in the right thalamus, right parietal lobe, and right cerebellum. These results suggested that weight gain during the process of recovery from early-onset AN might activate specific brain regions which are possibly relevant to the pathophysiological aspects of the disorder., (Copyright 2009 Elsevier B.V. All rights reserved.)

Cholecystokinin, produced in the proximal small intestine, is a short acting satiating peptide hormone. CCK-10, before and after mono-iodination, was previously coupled to 10kDa polyethylene glycol (PEG). The formed conjugates PEG10kDa-CCK-10 and PEG10kDa-[(127)I]-CCK-10 show after i.p. administration to rats a sustained food intake reduction during 8h in comparison to 2h for free CCK-10. The present study examined the blood pharmacokinetics of this pharmacological interesting molecule by means of PEG10kDa-[(123)I]-CCK-10 following intravenous, intraperitoneal, intramuscular and nasal administration and the biodistribution after i.p. administration. HPLC analysis with radiometric detection allowed the differentiation between inorganic iodide and the intact tracer in blood. Blood kinetics after i.v. injection was fitted to a bi-exponential with a distribution half-life of 15 min and with an elimination half-life of 8 hours for intact PEG10kDa-[(123)I]-CCK-10. The biodistribution studies showed a higher accumulation of the tracer for all administration routes in organs expressing CCK receptors localized in the gastrointestinal tract such as pancreas, duodenum and small intestine. No indication of blood brain barrier crossing for the conjugate could be observed independently of the administration route. Main clearance was via the urinary pathway.

The sheep has served as an informative animal model for investigation of human fetal and newborn erythropoiesis and red blood cell (RBC) kinetics. We previously validated the permanent label (14C)cyanate for measuring red cell volume (RCV) in sheep. Here, we validate biotin labeling of RBCs as a nonradioactive method for measuring RCV in sheep with the anticipation that it can be applied in studies of human infants. The RCV was determined simultaneously using two techniques for quantitation of the biotin label. The first one quantified total blood concentration of biotin label on biotin-labeled RBCs using (125I)streptavidin. The second one enumerated biotin-labeled RBCs by flow cytometry after incubation with fluorescein-conjugated avidin. RCV measurements made using the two biotin quantitation techniques were validated against both (14C)cyanate and 51Cr as reference methods. Both biotin techniques produced RCV values that agreed well with the reference methods and with each other, producing correlation coefficients averaging >or =0.93. Sequential repetitive measurements in the same animal also agreed with the (14C)cyanate method and each other (average difference <10%). These results establish biotin-labeled RBCs as an accurate method for performing RCV measurements in sheep. This biotin method can be applied in studies that model neonatal erythropoiesis.

Objective: The 4.2-day half-life of (124)I favors its use for positron emission tomography (PET) of monoclonal antibodies (mAbs). However, high positron energy and beta(+) -associated cascade gamma rays pose image resolution and background noise problems for (124)I. This study evaluated quantitative PET of an (124)I mAb in tumor-bearing mice., Methods: An R4 microPETtrade mark (Siemens/CTIMI, Knoxville, TN) was used with standard energy and coincidence timing windows (350-750 keV and 6 ns, respectively), delayed random coincidence subtraction, iterative image reconstruction, and no attenuation or scatter correction. Image resolution, contrast, and response linearity were compared for (124)I and (18)F, using phantoms. Nude mice bearing human colon tumors (LS-174T) were injected intravenously with a chimeric (124)I anti-CEA mAb (cT84.66) and imaged serially 1 hour to 7 days postinjection. Venous blood was sampled to validate image-derived blood curves. Mice were sacrificed after the final scan, and the biodistribution of (124)I was measured by direct tissue assay. Images were converted to units of kBq/g for each tissue of interest by comparing the final scans with the direct assays., Results: Measured resolution (FWHM) 0-16 mm from the scanner axis was 2.3-2.7 mm for (124)I versus 1.9-2.0 mm for (18)F. Due to true coincidence events between annihilation photons and cascade gamma rays, background was greater for (124)I than (18)F, but the signal-to-background ratio was still more than 20, and (124)I image intensities varied linearly with activity concentration. Tissue-based calibration worked well (i.e., PET blood curves agreed with direct measurements within 12% at all time points), while calibration, based on a cylindrical phantom approximating the mouse body, yielded tumor quantitation that was 46%-66% low, compared with direct assay., Conclusions: Images of quantitative accuracy sufficient for biodistribution measurements can be obtained from tumor-bearing mice by using (124)I anti-CEA mAbs with standard microPET acquisition and processing techniques, provided the calibration is based on the direct assay of excised tissue samples.

Mucopolysaccharidosis type IIIA (MPS IIIA), which is a lysosomal storage disorder (LSD) caused by inherited deficiency of sulfamidase, is characterized by severe, progressive central nervous system (CNS) dysfunction. Enzyme replacement therapy (ERT) to treat CNS storage is challenging, because the access of enzymes to the brain is restricted by the blood-brain barrier (BBB). In a prior study, we found that phosphorylated beta-glucuronidase (P-GUS) could be transcytosed across the BBB in newborn mice by the mannose 6-phosphate (M6P) receptor. In order to determine whether sulfamidase can utilize this pathway, we examined brain influx and the specificity of uptake of sulfamidase after intravenous (i.v.) injection in 2-day-old and 8-week-old mice. [(131)I]Sulfamidase was transported across the BBB in neonates at rates higher than that of simultaneously injected [(125)I]albumin. In contrast, the transport of [(131)I]sulfamidase was negligible in 8-week-old mice, thereby showing that the BBB transport mechanism is developmentally downregulated. Capillary depletion revealed that 83.7% of the [(131)I]sulfamidase taken up by the brain was in the parenchyma, demonstrating transfer across the capillary wall. The uptake of [(131)I]sulfamidase into the brain was significantly reduced by co-injections of M6P and P-GUS. That is, the transport of sulfamidase into the brain parenchyma in early postnatal life is mediated by the M6P receptor, which is shared with P-GUS and is likely accessible to other M6P-containing lysosomal enzymes.

The synthesis and investigation of 5-[125I]iodoindol-3-yl-beta-d-galactopyranoside ([125I]IBDG) as a radioligand for single-photon emission computed tomography (SPECT) imaging of b-galactosidase expression are described. No-carrier-added [125I]IBDG was synthesized by a radioiododestannylation approach in > 75% overall radiochemical yield and > 99% radiochemical purity. [125I]IBDG was evaluated as a substrate using beta-galactosidase-expressing (D54L) and nonexpressing (D54) human glioma cell lines. A 24-hour incubation of this substrate with cultured cells revealed a 6.5-fold greater intracellular trapping of radioactivity in D54L cells compared with D54 cells. Systemic delivery of [125I]IBDG in nude mice bearing D54L tumors failed to show significant trapping of radioactivity within these tumors by SPECT imaging. In contrast, intratumoral injection of the substrate resulted in efficient trapping of radioactivity in D54L tumors but not D54 tumors, resulting in clear SPECT visualization of the former tumor. Based on dynamic SPECT imaging and blood metabolite analysis, we conclude that although [125I]IBDG is an efficient in vivo substrate for beta-galactosidase, its rapid renal clearance hampers its intratumoral availability on systemic administration.

Tamoxifen [TAM ([Z]-2-[4-(1,2-diphenyl-1-di-butenyl)-phenoxy]-N,N-dimethylethanamine)] has been used as an antiestrogen drug for treatment and prevention of human breast cancer. Tamoxifen was labeled with 131I using iodogen as an oxidizing agent. Mass spectroscopy of the cold standard showed that the labeling occurs in ortho position to the phenyl ether position of TAM as expected. Quality control, radiochemical yield and stability were established using the radioelectrophoresis method. The radiolabeled compound maintained its stability throughout working period of 24 h. Scintigraphic imaging was performed and tissue distribution was determined in Albino Wistar rats. According to biodistribution and imaging experiments the radiolabeled compound presented estrogen receptor (ER) specificity and it was uptaken by endometrium as well as breast tissue.

In teleosts, the thyroid gland is mostly found in the subpharyngeal region. However, in several species thyroid follicles are found in, for example, heart, head kidney and kidney. Such heterotopic thyroid follicles are active, and considered to work in concert with the subpharyngeal thyroid. In Mozambique tilapia (Oreochromis mossambicus) thyroid activity is, indeed, restricted to the subpharyngeal region; in common carp (Cyprinus carpio) the functional endocrine thyroid is associated with renal tissues. The subpharyngeal follicles of carp comprise only 10% of the total thyroid tissue, and these follicles neither accumulate iodide nor synthesize or secrete thyroid hormones to a significant degree. Although the shape and size of carp subpharyngeal and renal follicles vary, the epithelial cell height of the thyrocytes and thyroxine immunoreactivity do not differ, which suggests that the activity of the carp subpharyngeal thyroid follicles is dormant. Differences in thyroid physiology between the two fish species were further assessed at the level of peripheral thyroid hormone metabolism. Carp clears plasma of thyroid hormones faster than tilapia does. Furthermore, a significant amount of conjugated thyroid hormones was observed in the plasma of tilapia, which was preceded by the occurrence of thyroid hormone conjugates in the subpharyngeal region and coincides with the appearance of conjugates in the surrounding water. Apparently, plasma thyroid hormone conjugates in tilapia originate from the thyroid gland and function in the excretion of thyroid hormones. Our data illustrate the variability in teleostean thyroidology, an important notion for those studying thyroid physiology.

Unlabelled: The aim of this study is to validate the ability of the disappearance model to predict absorption rates of insulin aspart in pigs. The disappearance model is used as a screening tool to estimate absorption rates after subcutaneous injections in humans or pigs especially of insulin and insulin analogues. The disappearance model measures remaining radioactivity at the injection site and therefore radioactive labelling of the insulin analogue is necessary. The labelling is done with 125I. One of the assumptions for the disappearance model to be reliable is that absorption rates of the labelled and non-labelled molecules are comparable. In this study, we compared disappearance data with absorption calculated from plasma samples of insulin aspart. The calculated absorption is based on non-labelled insulin aspart. The absorption rate from the disappearance data was statistical significant (p = 0.0028) different from the absorption rate based on plasma samples. A control study was carried out where 125I labelled insulin aspart was compared to 127I (the natural non-radioactive isotope) insulin aspart. In this study, absorption rate from the disappearance data and absorption rate based on plasma samples were similar (p = 0.63)., Conclusion: Iodination of insulin aspart changes the subcutaneous absorption rate.

Unlabelled: Free 211At has been proposed for therapy of anaplastic thyroid carcinoma (ATC). However, no extensive biodistribution study comparing tumor-bearing and nontumor-bearing mice has previously been performed. The aim of this study was to perform a complete evaluation of the biodistribution of 211At, both for normal and ATC-bearing mice. For comparison, the biodistribution of 125I- was simultaneously studied. Dosimetric evaluations were performed to investigate if (211)At can be used for therapy of ATC., Methods: Athymic nude mice were subcutaneously injected with either of two human ATC cell lines, HTh83 and KAT-4. Tumor-bearing and nontumor-bearing mice were injected intravenously with 0.3 MBq 211At and 0.3 MBq 125I- simultaneously. The mice were sacrificed 4-24 hours after injection, and the activity concentrations in tissues were determined., Results: Except for the thyroid, the concentration of 211At was higher than that of 125I- in the tissues. The uptake of 211At was primarily high in NIS-expressing organs. Furthermore, the absorbed doses to these organs were higher than both tumor types., Conclusions: The biodistribution of 211At and 125I- differed in this animal model. The higher mean absorbed dose from 211At in several organs than in tumor tissue restricts the possibility of using free 211At for therapy of ATC.

Background: Local recurrence, the most frequent pattern of recurrence of rectal carcinoma, is almost always fatal. The difficulty of diagnosing local recurrence contributes importantly to the poor prognosis., Methods: We coupled monoclonal antibody (Mab) A7, which reacts specifically with human colorectal carcinoma, to ferromagnetic lignosite (FML) particles to distinguish rectal carcinoma from other tissues by magnetic resonance (MR) imaging. We examined retention of immunoreactivity by the A7-FML complexes in vitro, and also their distribution in vivo according to radiolabeling and MR imaging when injected into nude mice bearing human colorectal carcinoma xenografts., Results: A7-FML retained binding activity nearly identical to that of Mab A7. Significantly more (125)I-labeled A7-FML accumulated in engrafted tumors than did (125)I-labeled normal mouse IgG-FML complexes (P < 0.05). A7-FML disappeared rapidly from the blood. Normal tissues accumulated less (125)I-labeled A7-FML than tumors; this accumulation decreased linearly with time. In MR imaging, signal intensity was reduced in the tumor by the injection of A7-FML., Conclusions: A7-FML is potentially useful as a MR contrast enhancing agent for human colorectal carcinoma xenografts implanted subcutaneously.

Objectives: Patients treated by (131)I may require blood sampling in the days following its administration. We investigated the safety of such samples in terms of radioactivity and the possible disturbance of the analyses by these "131I-spiked" samples., Method: 1) The radioactivity of blood samples from 131I-treated patients was measured (dose rate, surface activity, total activity) ; 2) The risk for the personnel was subsequently evaluated and ; 3) The interference of this 131I-generated radioactivity on the results of routine automated and IRMA assays was investigated., Results: 1) All RA measures but two were found below the European limits ; 2) Irradiation of personnel was negligible ; 3) The faint radioactivity did not disturb any analyses., Conclusion: These data demonstrate the safety that results from the negligible radioactivity in these blood samples.

Objective: Our objective was to investigate the safety of radioactive blood samples from patients receiving 131I and whether the radioactivity affects the validity of assays., Methods: First, the activity of samples from patients given 131I was measured by 3 methods and compared with the upper threshold. Then, pilot sera were spiked with 131I, and possible interference was investigated using 2 immunoradiometric assays., Results: The activity of 13 of the 15 samples was below the European limit; the other 2 samples were from patients with reduced renal clearance rates. No differences in thyroglobulin level or thyroid-stimulating hormone level were found between sera that were spiked with 131I and sera that were not., Conclusion: These blood samples are safe because they contain negligible activity, and the use of radioimmunoassays or immunoradiometric assays on them produces reliable results.

Unlabelled: Aim of this study was to find out, if results of a functional orientated radioiodine therapy in Graves' disease could be optimized using a risk adopted dose concept., Patients, Method: 351 patients with Graves' disease were treated for the first time between 11/97 and 8/01. The basic dose was 125 Gy, which was increased up to 250 Gy in a cumulative manner depending on clinical parameters (initial thyroid metabolism, thyroid volume, immunoreactivity). Two different methods of dosimetry were used. Occasional thyreostasis was withdrawn two days before the radioiodine test was started. Follow up was done on average 8 +/- 2.4 (4-17.2) months. TSH > or = 0.27 microIU/mL confirmed as a measure of the success., Results: With improved pretherapeutic dosimetry and a mean target dose of 178 +/- 31 Gy (n=72) therapeutic success occurred in 66.7%, in 51.4% euthyreosis was restalled and in 15.3% of patients hypothyroidism was seen (TSH > 4.20 microIU/mL). With simplified pretherapeutic dosimetry and a mean target dose of 172 +/- 29 Gy (n=279) results were moderately impaired (63.8%, 40.1% and 23.7%). With increasing target dose therapeutic failure increased, as insufficiently adopted risk factors for therapeutic failure turned out the initial thyroid metabolism, the TcTU(s) as the (h)TRAb titer., Conclusion: Functional orientated RIT can be optimized by including illness specific characteristics, principal limitations are a high initial thyroid metabolism, a large thyroid volume and a high (h)TRAb-titer.

Detection of perchlorate (ClO4-) in several drinking water sources across the U.S. has lead to public concern over health effects from chronic low-level exposures. Perchlorate inhibits thyroid iodide (I-) uptake at the sodium (Na+)-iodide (I-) symporter (NIS), thereby disrupting the initial stage of thyroid hormone synthesis. A physiologically based pharmacokinetic (PBPK) model was developed to describe the kinetics and distribution of both radioactive I- and cold ClO4- in healthy adult humans and simulates the subsequent inhibition of thyroid uptake of radioactive I- by ClO4-. The model successfully predicts the measured levels of serum and urinary ClO4- from drinking water exposures, ranging from 0.007 to 12 mg ClO4-/kg/day, as well as the subsequent inhibition of thyroid 131I- uptake. Thyroid iodine, as well as total, free, and protein-bound radioactive I- in serum from various tracer studies, are also successfully simulated. This model's parameters, in conjunction with corresponding model parameters established for the male, gestational, and lactating rat, can be used to estimate parameters in a pregnant or lactating human, that have not been or cannot be easily measured to extrapolate dose metrics and correlate observed effects in perchlorate toxicity studies to other human life stages. For example, by applying the adult male rat:adult human ratios of model parameters to those parameters established for the gestational and lactating rat, we can derive a reasonable estimate of corresponding parameters for a gestating or lactating human female. Although thyroid hormones and their regulatory feedback are not incorporated in the model structure, the model's successful prediction of free and bound radioactive I- and perchlorate's interaction with free radioactive I- provide a basis for extending the structure to address the complex hypothalamic-pituitary-thyroid feedback system. In this paper, bound radioactive I- refers to I- incorporated into thyroid hormones or iodinated proteins, which may or may not be bound to plasma proteins.

Unlabelled: Standardization of marrow dosimetry is of considerable importance when estimating dose-response for a multicentered clinical trial involving radionuclide therapy. However, it is only within the past five years that the intercomparison of marrow dosimetry results among separate clinical trials that use the same agent has become scientifically feasible. In this work, we have analyzed reported marrow dosimetry results from radioimmunotherapy trials and recalculated marrow absorbed doses at a central facility using a standard blood model with patient-specific source data. The basic approach used in the American Association of Physicists in Medicine (AAPM)/Sgouros marrow dosimetry methodology was common to calculation performed at all participating institutions, including the central facility. Differences in dose estimates associated with starting assumptions and the exact implementation of the AAPM/Sgouros calculation methodology used by the source institutions and the central facility were quantified and compared., Methods: Data from 22 patients enrolled in radiolabeled antibody clinical trials were randomly selected from 7 participating institutions for the assessment of marrow dose. The analysis was restricted to those patients who were treated with 131I- or 186Re-labeled antibody and had no marrow involvement. Calculation of bone marrow dose at each participating institution was unique to the trial or institution, but all used some form of the AAPM/Sgouros blood model approach. The central facility adopted a marrow dosimetry model based on the AAPM/Sgouros model for radiolabeled antibodies using the standard MIRD approach to the remainder-of-body contribution. A standardized approach to account for variations in patient mass was used for the remainder-of-body component. To simplify clinical implementation, regional marrow uptake and time-dependent changes in the marrow-to-blood concentration ratio were not included. Methods of formatting the collection of standard datasets useful in defining dose-response parameters are also presented., Results: Bone marrow doses were calculated according to the method described for each of the 22 patients based on the patient-specific data supplied by the participating institutions. These values were then individually compared with the marrow doses originally reported by each institution. Comparison of the two calculation methods was expressed as a ratio of the marrow doses for each patient. The mean ratio for the dose estimates at the participating institution calculation compared with the central laboratory value was 0.920 +/- 0.259 (mean +/- SD), with a range from 0.708 to 1.202., Conclusion: The independent use of the AAPM/Sgouros method blood model approach to marrow dosimetry has brought these dose estimates to within 30% of the results obtained centrally compared with substantially higher uncertainties reported previously. Variations in calculation methodology or initial assumptions adopted by individual institutions may still contribute significant uncertainty to dose estimates, even when the same data are used as a starting point for the calculation comparison shown here. A clinically relevant, standard method for marrow dosimetry for radiolabeled antibodies is proposed as a benchmark for intercomparison purposes. A parameter sensitivity analysis and a summary discussion of the use of this model for potentially improving dose-response data correlation are also presented.

We experienced a case with Graves' disease in which radioiodine treatment failed probably because of intentional spitting out of capsules of radioactive iodide. Chemical analysis of the substances collected from the trash in the treatment room demonstrated that its profile was the same as that of the capsules for radioiodine administration. Measurement of the iodine concentrations in a blood sample obtained at 24 h after the administration of radioiodine indicated that the patient showed iodine excess. These findings suggest that this may be a case of Munchausen syndrome.

Quantification of uncertainties in doses from intakes of radionuclides is important in risk assessments and epidemiologic studies of individuals exposed to radiation. In this study, the uncertainties in the doses per unit intake (i.e., dose coefficients) for ingestion of 131I, 137Cs, and 90Sr by healthy individuals have been determined. Age-dependent thyroid dose coefficients were derived for 131I. The analysis for 131I uses recent measurements of thyroid volume obtained by ultrasonography, which indicate a thyroid mass lower than that previously obtained using autopsy measurements. The coefficients for 137Cs are determined using the relationship between the biological half-lives and the amount of potassium in the human body. The most recent International Commission on Radiological Protection biokinetic model was employed to determine the uncertainties for 90Sr. For 137Cs and 90Sr, the dose coefficients represent exposure in adulthood and they were determined for all organs of radiological importance. The uncertainty in the estimated dose coefficients represent state of knowledge estimates for a reference individual, and they are described by lognormal distributions with a specified geometric mean (GM) and geometric standard deviation (GSD). The estimated geometric means vary only slightly from the dose coefficients reported by ICRP publications. The largest uncertainty is observed in the dose coefficients for bone surface (GSD = 2.6), and red bone marrow (GSD = 2.4) in the case of ingestion of 90Sr. For most other organs, the uncertainty in the 90Sr dose coefficients is characterized by a GSD of 1.8 (or less for some organs). For 131I, the uncertainty in the thyroid dose coefficients is well represented by a GSD of 1.7 for both sexes and all ages other than infants for whom a GSD of 1.8 is more appropriate. The lowest uncertainties are obtained for the dose coefficients from ingestion of 137Cs (GSD = 1.24 for males; 1.4 for females). A dominant source of uncertainty in the ingestion dose coefficients is the variation of the biokinetic parameters. For 131I, the largest contribution to the uncertainty comes from the variation in the thyroid mass, but the contribution of the biokinetic parameters is comparable. The biokinetic parameters with the largest contribution to the uncertainty are (a) the fractional uptake from blood to thyroid in the case of ingestion of 131I, (b) the absorbed fraction from the gastrointestinal tract (f1) in the case of 90Sr, and (c) the amount of potassium in the body for 137Cs. The contribution to the uncertainty of the absorbed fraction (which accounts for the fraction of energy deposited in the target organ) is the smallest contributor to the uncertainty in the dose coefficients for most organs. To reduce the uncertainty in the dose estimated for a real individual, one should determine the above-mentioned parameters for the specified individual rather than to rely on assumptions for a reference individual.

Unlabelled: One approach to treatment of primary hepatocellular carcinoma (HCC) is intraarterial injection of (131)I-lipiodol. Although clinical results have been positive, the therapy can be improved by using (188)Re instead of (131)I as the radionuclide. (188)Re is a high-energy beta-emitter, has a shorter half-life than (131)I, and has only low-intensity gamma-rays in its decay. The present study compared the cytotoxic effect of the radionuclide therapy in HCC patients treated with (131)I-lipiodol and (188)Re-4-hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD)/lipiodol. To this end, dicentric chromosomes (DCs) were scored in metaphase spreads of peripheral blood cultures. The equivalent total-body dose was deduced from the DC yields using an in vitro dose-response curve., Methods: Twenty (131)I-lipiodol treatments and 11 (188)Re-HDD/lipiodol treatments were performed on, respectively, 16 and 7 patients with inoperable HCC. Patients received a mean activity of 1.89 GBq of (131)I-lipiodol or 3.56 GBq of (188)Re-HDD/lipiodol into the liver artery by catheterization. For each patient, a blood sample was taken during the week before therapy. A blood sample was also taken 7 and 14 d after administration for the patients treated with (131)I-lipiodol and 1 or 2 d after administration for the patients treated with (188)Re-HDD/lipiodol., Results: The mean DC yield of (188)Re-HDD/lipiodol therapy (0.087 DCs per cell) was significantly lower than that of (131)I-lipiodol therapy (0.144 DCs per cell) for the administered activities. Corresponding equivalent total-body doses were 1.04 Gy for (188)Re-HDD/lipiodol and 1.46 Gy for (131)I-lipiodol. Data analysis showed that, in comparison with (131)I-lipidol, (188)Re-HDD/lipiodol yielded a smaller cytotoxic effect and a lower radiation exposure for an expected higher tumor-killing effect., Conclusion: (188)Re is a valuable alternative for (131)I in the treatment of HCC with radiolabeled lipiodol, and a dose escalation study for (188)Re-HDD/lipiodol therapy is warranted.

We have previously performed quantitative kinetic modeling of [(123)I]CNS 1261, a new SPET ligand for the MK801 intrachannel site of the NMDA receptor. We now report a bolus-infusion protocol, which eliminates the need for arterial blood sampling. Dynamic SPET scanning and venous blood sampling were performed in 7 healthy volunteers. Good agreement was obtained between kinetic and equilibrium analysis. SPET scanning with a bolus-infusion protocol is a valid method to estimate the total volume of distribution for [(123)I]CNS 1261 in clinical populations.

The dose limiting factor for 131I therapy in patients with thyroid cancer is myelotoxicity, thus an accurate determination of radioiodine activity in the red marrow is of paramount importance. The reference method for red marrow dosimetry in radiometabolic therapy is based on the measurement of radioiodine kinetics, particularly the activity/time curve in blood. Such a measurement requires withdrawal of blood samples at various times after 131I administration. This procedure involves some potential risk from the radiation protection point of view, such as possible contamination of personnel with blood and disposal of the radioactive blood samples (and syringes). We present here a minimally invasive method to evaluate radioiodine kinetics in the blood, which only requires one blood sample and a set of measurements on the patient's thigh made with a collimated NaI(Tl) probe. The method has been validated in four patients treated with 131I for thyroid cancer., (Copyright 2004 Oxford University Press)

Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT(4)) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT(4) receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT(4) receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT(4) receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [(123)I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT(4) receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT(4) receptor antagonist, SB 204070, at 20 min before [(123)I]SB 207710 injection. Radioactivity in all brain regions was reduced almost to the level in cerebellum by 176 min after radioligand injection. These findings show that [(123)I]SB 207710 is an effective radioligand for imaging brain 5-HT(4) receptors in vivo.

Iodine kinetics were studied in patients with differentiated thyroid cancer while euthyroid under exogenous thyroid stimulating hormone (TSH) and while hypothyroid to detect differences in radioiodine uptake, distribution and elimination. Nine patients with total or near-total thyroidectomy on thyroid hormone suppressive therapy received two or three daily doses of 0.9 mg recombinant human TSH (rhTSH) followed by administration of a diagnostic activity of 2 mCi (74 MBq) iodine-131. After the biokinetics assessments had been performed, patients stopped taking thyroid hormones to become hypothyroid. A second 2 mCi (74 MBq) diagnostic activity of 131I was administered, followed by a second set of biokinetics assessments. One week later the patients underwent remnant ablation with a therapeutic activity of 131I. A comparison of the 131I kinetics in the patients while euthyroid and while hypothyroid showed major differences in the doses to the remnant as well as in residence times and radiation exposure to the blood. In the first diagnostic assessment the remnant dose was higher in eight of the nine patients and clearance of the activity from the blood was faster in all of them. The data from this study suggest that radioiodine administration is potent and safe when administered to euthyroid patients following rhTSH administration. Enhanced residence time in the remnant and decreased radiation exposure to the blood were noted when patients were euthyroid compared to when they were rendered hypothyroid. However, all patients received diagnostic activities in the same order: first while euthyroid, followed by hypothyroidism. It is quite possible that "stunning" from the radioiodine administered in the initial uptake study inhibited the subsequent uptake of radioiodine by the remnant lesions in the second uptake study.

Unlabelled: Radioimmunotherapy (RIT) is a new and effective treatment modality in patients with non-Hodgkin's lymphoma. The monoclonal antibody (mAb) hLL2 (epratuzumab), a humanized mAb directed against the CD22 antigen, and which internalizes, can be labeled with various radionuclides. The biodistribution of hLL2 labeled with (131)I, (186)Re, (177)Lu, and (88)Y was studied in nude mice with subcutaneous human lymphoma xenografts in order to determine the most suitable of these four radionuclides for RIT with hLL2., Methods: Human Ramos lymphoma xenografts were transplanted in cyclophosphamide-pretreated athymic BALB/c mice. Four groups of mice were injected intravenously with (131)I-, (186)Re-, (88)Y-, or (177)Lu-labeled hLL2, respectively. To determine the nonspecific tumor uptake, two groups of mice received (88)Y-labeled or (131)I-labeled control antibody, cG250. The biodistribution of the radiolabel was determined 1, 3, and 7 days postinjection (p.i.)., Results: Radiolabeled hLL2 had a higher tumor uptake than the nonspecific mAb at all time-points, irrespective of the radiolabel used. Tumor accretion of (88)Y- and (177)Lu-hLL2 was higher than tumor uptake of (131)I- and (186)Re-hLL2. Activity in the bone, represented by the femur without bone marrow, was higher for (177)Lu- and (88)Y-hLL2 than for (131)I- and (186)Re-hLL2 on day 7 p.i., Conclusion: The use of the residualizing radiolabels (88)Y and (177)Lu in combination with a mAb directed against an internalizing antigen resulted in higher uptake and better retention of the radiolabel in the tumor.

Angiostatin (AS) is a potent antiangiogenic agent which inhibits tumor growth through specific action on proliferating endothelial cells. Imaging of radiolabeled AS would enhance our knowledge on the pharmacokinetics of AS and might provide useful information relating to tumor neovasculature. We therefore investigated the potential of radiolabeled AS as a novel tumor imaging agent. Human angiostatin was radioiodine labeled using the lactoperoxidase method. Competition binding studies showed a dose-dependent inhibition of (125)I-AS binding to endothelial cells by excess unlabeled AS, and a displacement curve demonstrated that specific binding was dose dependent and saturable, with a K(d) value of 169 n M. Gel analysis showed that (125)I-AS remained stable in serum for up to 24 h without significant degradation. Intravenously injected (125)I-AS in rats was cleared from the blood in an exponential fashion. Biodistribution data from human colon cancer-bearing Balb/C nude mice showed high uptake in the kidneys, stomach, liver, and lungs. Tumor uptake was 3.2+/-0.7, 2.6+/-0.2, and 1.7+/-0.2%ID/g at 2, 4, and 9 h after injection, respectively. Tumor to muscle count ratio increased from 3.1+/-0.5 at 2 h to 4.4+/-0.5 at 9 h. Serial scintigraphy from 1 to 5 h after (123)I-AS injection demonstrated high uptake in the kidneys and bladder, consistent with renal excretion. There was clear demarcation of tumor by 1 h, with gradual increase in contrast over time (4-h tumor to contralateral thigh ratio =4.7+/-1.1). Thus, radioiodine-labeled angiostatin binds specifically to endothelial cells and has potential as a novel tumor imaging agent.

Although in vitro theory indicates that ligand binding is sensitive to competition with neurotransmitters, only some imaging ligands have shown such competition in vivo. The purpose of this study was to determine whether increases in acetylcholine (ACh) levels induced by an acetylcholinesterase inhibitor, physostigmine, inhibit in vivo binding of [(123)I]5-iodo-3-(2(S)-2-azetidinyl-methoxy) pyridine (5-I-A-85380), a single photon emission computed tomography ligand for the high-affinity type nicotinic ACh receptor (nAChR). Baboons were used for seven studies with a bolus plus constant infusion equilibrium paradigm. After achieving equilibrium at 5 h, physostigmine (0.02 (n = 1), 0.067 (n = 3), and 0.2 (n = 3) mg/kg) was administered intravenously and data were acquired for up to 8 h. To confirm equilibrium conditions, [(123)I]5-I-A-85380 plasma levels were measured in four studies, including all studies with 0.2 mg/kg physostigmine. Prior to physostigmine administration, thalamic activities were stable, with changes of 1.1%/h or less, except in one study with a gradual increase of 4.2%/h. Thalamic activities were decreased by 15% in one study with 0.067 mg/kg and 14-17% in all studies with 0.2 mg/kg physostigmine administration (P = 0.009). In these studies with 0.2 mg/kg physostigmine administration, [(123)I]5-I-A-85380 plasma levels showed a transient or a sustained increase after physostigmine administration that would have increased thalamic activities. These results suggest that elevated ACh levels induced by physostigmine can effectively compete in vivo with [(123)I]5-I-A-85380 binding at nAChRs. However, decreased thalamic activities could have been caused by other mechanisms, including internalization of the receptor with an associated decreased affinity for radioligand., (Copyright 2003 Wiley-Liss, Inc.)