Stereo Selective Synthesis,Characterization, and Application of d-Ritalinic Acid as Renal Imaging Agent in Nuclear Medicine

Purpose

Renal imaging is a well-established technique in nuclear medicine. The renal imaging agents used in the current methods have some drawbacks as they take lot of time so as to produce good quality images. Hence, newer renal imaging agents were explored that can reduce the time taken to produce quality images.

Methods

dl-Ritalinic acid (dlRA) was synthesized and d- and l- isomers were separated by resolution using resolving agent, (+)-dibenzoyl-D-tartaric acid. The purity of d-ritalinic acid (dRA) was determined by HPLC analysis and the structure was characterized by spectroscopic techniques (IR, mass, NMR). The complex, ^99mTc-dRA, was prepared by the addition of ^99mTc sodiumpertechnetate using stannous chloride dihydrate as reducing agent. The various factors which affect the radiolabeling efficiency such as reaction time, amount of ligand (dRA), reducing agent, anti-oxidant, and pH of reaction medium were studied. Radiochemical purity and in vitro stability of the labeled complex, ^99mTc-dRA, were studied using ascending paper chromatography in saline and acetone media. Biodistribution studies of the complex (^99mTc-dRA) and commercially available renal imaging agents (^99mTc-DTPA and ^99mTc-EC) in Wistar rats were studied by drawing region of interest over the organs without sacrificing the animal and the results were compared.

Results

Radiochemical purity of ^99mTc-dRA was found to be 95.65?±?3.36% at a pH range of 5.5–6.5 and was stable up to 6 h at room temperature. The optimum labeling was found to be in the ratio of 1:4:0.5 of ligand (dRA), ascorbic acid, and stannous chloride dihydrate.

Conclusion

Compared to commercial renal imaging agents (^99mTc-DTPA and ^99mTc-EC), the synthesized complex, ^99mTc-dRA, showed high target to non-target (T/NT) counts, clear images in early stages and is harmless as it is a metabolite of drug already taken up by body organs.

     

Novel Benzofurans with 99mTc Complexes as Probes for Imaging Cerebral β-Amyloid Plaques

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Synthesis and biodistribution of novel 99mTc‐nitrido methylpiperidine dithioformate derivatives as potential brain imaging agents

Three dithioformate ligands with methyl substituted on the piperidine rings, potassium 1‐(2‐methylpiperidine‐1‐yl)‐dithioformate (2‐mp), potassium 1‐(3‐methylpiperidine‐1‐yl)‐dithioformate (3‐mp) and potassium 1‐(4‐methylpiperidine‐1‐yl)‐dithioformate (4‐mp) were synthesized. The corresponding ^99mTc‐nitrido complexes were prepared in high yield (>95%) through the [^99mTcN] intermediate and characterized by thin layer chromatography and high‐performance liquid chromatography. All the neutral ^99mTc‐nitrido complexes were stable under physiological conditions and lipophilic with log P values between 1.40 and 1.58. In vivo biodistribution results showed that all the ^99mTc‐nitrido complexes displayed high brain uptakes and long retention times. Among them, ^99mTcN‐4mp, demonstrated the best properties for brain imaging with the brain uptake 3.40±0.24, 3.22±0.31, 2.72±0.28 and 2.22±0.18% ID/g at 5, 30, 60 and 120 min p.i., respectively. Moreover, the influence of stereochemistry of the ^99mTcN complexes with methyl substitution on ortho, meta and para positions on piperidine ring on the biodistribution properties were investigated with B3LYP/6‐31G*(LANL2DZ for Tc) method using the Gaussian 03 program package. Copyright © 2009 John Wiley & Sons, Ltd.     

Evaluation of a 99mTc-Labeled AnnexinA5 Variant for Non-invasive SPECT Imaging of Cell Death in Liver, Spleen and Prostate

Purpose

We investigate radio-labeling and pharmacokinetics of a new AnnexinA5 variant (HYNIC-cys-AnxA5) and then assess its utility for the non-invasive detection of cell death in liver, spleen and prostate.

Methods

AnnexinA5 binds to phosphatidylserine expressed on the surface of apoptotic and necrotic cells. Contrary to other AnnexinA5 variants, the new cys-AnxA5 allows for site-specific conjugation of a hydrazinonicotinamide-maleimide moiety and subsequent radio-labeling with ^99mTc at a position not involved in the AnxA5-phosphatidylserine interaction. Distribution of ^99mTc-HYNIC-cys-AnxA5 was studied in rats, both invasively and via SPECT/CT. Cycloheximide was used to induce cell death in liver and spleen, whereas apoptosis in the prostate was induced by castration.

Results

HYNIC-cys-AnxA5 was efficiently and reproducibly labeled with ^99mTc. Blood clearance of radioactivity after iv-injection was adequately described by a two-compartment model, the renal cortex representing the main site of accumulation. Cycloheximide treatment resulted in increased accumulation of intravenous-injected ^99mTc-HYNIC-cys-AnxA5 in liver and spleen over controls, which correlated well with TUNEL staining for cell death in corresponding tissue sections. However, the increase in TUNEL-positive prostate epithelial cells observed following castration was not paralleled by greater ^99mTc-HYNIC-cys-AnxA5 accumulation.

Conclusion

^99mTc-HYNIC-cys-AnxA5 appears a suitable tracer for assessment of cell death in liver and spleen, but not prostate.     

Application of 99Mo/99mTc alumina generator in the labeling of metoprolol for diagnostic purposes

Labeling of metoprolol by technetium‐99m in pertechnetate form (^99mTcO) eluted from a ⁹⁹Mo/^99mTc alumina generator in the presence of stannous chloride dihydrate was carried out via chelation reaction. The reaction parameters that affect the labeling yield such as metoprolol concentration, stannous chloride dihydrate concentration, reaction temperature, and pH of the reaction mixture were studied to optimize the labeling conditions. Using 1 GBq ^99mTcO, 500 µg metoprolol as substrate dissolved in 500 µL phosphate buffer at pH 9 and 50 µL of stannous chloride as reducing agent (1 mg/mL) at 25°C for 30 min reaction time, a maximum radiochemical yield of ^99mTc‐metoprolol (92%) was obtained. ^99mTc‐metoprolol was characterized by thin layer chromatography (TLC) and by high pressure liquid chromatography (HPLC). The specific activity of ^99mTc‐metoprolol obtained was 888 MBq/1.88 mmol. The biological distribution in normal mice showed that ^99mTc‐metoprolol is rapidly concentrated after injection in the heart, which indicates its suitability for heart imaging. Copyright © 2009 John Wiley & Sons, Ltd.     

The pharmacokinetics of oxypurinol in people with gout

AIMS

Our aim was to identify and quantify the sources of variability in oxypurinol pharmacokinetics and explore relationships with plasma urate concentrations.

METHODS

Non-linear mixed effects modelling was applied to concentration–time data from 155 gouty patients with demographic, medical history and renal transporter genotype information.

RESULTS

A one compartment pharmacokinetic model with first order absorption best described the oxypurinol concentration–time data. Renal function and concomitant medicines (diuretics and probenecid), but not transporter genotype, significantly influenced oxypurinol pharmacokinetics and reduced the between subject variability in the apparent clearance of oxypurinol (CL/F_m) from 65% to 29%. CL/F_m for patients with normal, mild, moderate and severe renal impairment was 1.8, 0.6, 0.3 and 0.18 l h⁻¹, respectively. Model predictions showed a relationship between plasma oxypurinol and urate concentrations and failure to reach target oxypurinol concentrations using suggested allopurinol dosing guidelines.

CONCLUSIONS

In conclusion, this first established pharmacokinetic model provides a tool to achieve target oxypurinol plasma concentrations, thereby optimizing the effectiveness and safety of allopurinol therapy in gouty patients with various degrees of renal impairment.     

In-vitro red blood cell partitioning of doxycycline

Objective:

In-vitro red blood cell (RBC) partitioning of doxycycline was studied to determine whether doxycycline penetrates RBC and its concentration was assayed keeping in view its high lipophilicity.

Materials and Methods:

Standardization of doxycycline was performed in whole blood and plasma of cattle by microbiological assay using Bacillus subtillis ATCC 6633 as indicator organizm. Actual concentration of the drug was obtained by comparing zone inhibition with standard graph and the extent of partitioning was mathematically calculated.

Results:

The R² value of standard graph for doxycycline was 0.9934 and 0.9727 for plasma and whole blood, respectively. Overall, RBC partitioning of doxycycline was found to be 18.40 ± 1.70%.

Conclusions:

Overall RBC partitioning of doxycycline indicated low penetration into RBC. Plasma is the fluid suggested for pharmacokinetic evaluation of doxycycline.     

Kit with technetium‐99m labelled antimicrobial peptide UBI 29‐41 for specific infection detection

The purpose of this study was to investigate radiochemical and biological characteristics of an instant kit for the preparation of ^99mTc‐labelled UBI 29‐41 for specific detection of infections. The kit is based on ^99mTc‐labelling via HYNIC conjugated to the terminal amine of the peptide, producing a well‐understood labelled compound. One hour after the addition of fresh ^99mTcO to the kit ITLC and HPLC reverse‐phase analysis was performed. Stability of the labelled complex was challenged and the binding to bacterial pellets was assessed. Finally, the biodistribution and accumulation in MRSA‐infected tissues were studied using scintigraphy and ex vivo countings. Data were compared to a non‐kit control method. Radiochemical analysis indicated >96% labelling, stability for 24 h and the preparation was used without purification. In vitro studies showed 41% of radioactivity was bound to bacteria. After injection into mice with a bacterial infection the site of infection was visualized within 30 min. Kit prepared ^99mTc‐HYNIC‐UBI 29‐41 was rapidly (half‐life 113 min) cleared via the kidneys and urinary bladder, essentially slower than control peptide (half‐life 74 min). This slower clearance results in higher activities in blood and other tissues. Nevertheless, ^99mTc‐HYNIC‐UBI 29‐41 shows favourable radiochemical characteristics and deserves further evaluation in a clinical setting. Copyright © 2005 John Wiley & Sons, Ltd.     

Evaluation of effect of allopurinol and febuxostat in behavioral model of depression in mice

Objective:

To evaluate the effects of allopurinol and febuxostat on depression using Forced Swim Test (FST) in mice.

Materials and Methods:

Allopurinol (39 mg/kg p. o) and febuxostat (15.6 mg/kg p. o) were administered once daily for 21 successive days to Swiss Albino mice. On the 21^st day, the effect of the drug on locomotion was tested using photo-actometer followed by the recording of immobility period in the FST and the results were compared with the standard drug fluoxetine (10 mg/kg p. o).

Results:

Allopurinol and febuxostat expressed significant antidepressant like effect as indicated by reduction in the immobility period of mice in the FST as compared to control group. The effects of allopurinol and febuxostat were found to be comparable to that of fluoxetine.

Conclusion:

The results of the present study indicate that allopurinol and febuxostat possess significant antidepressant like activity.KEY WORDS: Forced swim test, photo-actometer, serotonin, tryptophan     

Reproductive toxicity of sodium valproate in male rats

Objectives:

To assess the effects of sodium valproate on rat sperm morphology, sperm count, motility, and histopathological changes in testis.

Materials and Methods:

Male Wistar rats (12 week old) were treated with sodium valpraote and sacrificed at the end of 2^nd, 4^th, 5^th, 7^th, 10^th and 15^th week after the last exposure to sodium valproate. Epididymal sperm count, sperm motility, sperm morphology, and histopathology of testes were analyzed.

Results:

Sperm count and sperm motility were decreased significantly by sodium valproate. The percentage of abnormal sperms increased in a dose-dependent manner. A histopathological study revealed that sodium valproate had caused sloughing of epithelial cells in testes.

Conclusion:

Sodium valproate causes reversible change in sperm motility, sperm count, morphology, and cytoarchitecture of testes.     

Development of a radioiodinated apoptosis-inducing ligand, rhTRAIL, and a radiolabelled agonist TRAIL receptor antibody for clinical imaging studies

BACKGROUND AND PURPOSE

The TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis through activation of the death receptors, TRAIL-R1 and TRAIL-R2. Recombinant human (rh) TRAIL and the TRAIL-R1 directed monoclonal antibody mapatumumab are currently clinically evaluated as anticancer agents. The objective of this study was to develop radiopharmaceuticals targeting the TRAIL-R1, suitable for clinical use to help understand and predict clinical efficacy in patients.

EXPERIMENTAL APPROACH

rhTRAIL was radioiodinated with ¹²⁵I, and conjugated mapatumumab was radiolabelled with ¹¹¹In. The radiopharmaceuticals were characterized, their in vitro stability and death receptor targeting capacities were determined and in vivo biodistribution was studied in nude mice bearing human tumour xenografts with different expression of TRAIL-R1.

KEY RESULTS

Labelling efficiencies, radiochemical purity, stability and binding properties were optimized for the radioimmunoconjugates. In vivo biodistribution showed rapid renal clearance of [¹²⁵I]rhTRAIL, with highest kidney activity at 15 min and almost no detectable activity after 4 h. Activity rapidly decreased in almost all organs, except for the xenografts. Radiolabelled mapatumumab showed blood clearance between 24 and 168 h and a reduced decrease in radioactivity in the high receptor expression xenograft.

CONCLUSIONS AND IMPLICATIONS

rhTRAIL and mapatumumab can be efficiently radiolabelled. The new radiopharmaceuticals can be used clinically to study pharmacokinetics, biodistribution and tumour targeting, which could support evaluation of the native targeted agents in phase I/II trials.     

Quality control methods for 99mTc‐labeled exogenous natural surfactant (99mTc‐ENS)

To standardize the quality control for ^99mTc‐ENS, the following methods were studied: (1) physical properties and pH, (2) radiochemical purity (chromatographic studies on Whatman‐1 paper, or instant thin‐layer chromatography and solvent extraction using different solvents and (3) rat biodistribution studies by intratracheal injection. The tolerance limits were fixed for each method. The radiopharmaceutical stability was also evaluated. The results showed that ^99mTc‐ENS was a white suspension with a pH between 4.0 and 6.0. The limit for radiochemical impurities in Whatman‐1 paper/acetone was fixed at lower than 2% and the established limit for the organic aliquot in cyclohexane extraction was greater than 2%. In the biodistribution studies, the limits for activity concentration were fixed at greater than 90% for lungs, less than 9% for the gastrointestinal system and less than 1% for the sum of the other organs studied. After a storage time of 6 h at room temperature or in a refrigerator, ^99mTc‐ENS physical properties and pH, radiochemical and biodistribution results were within the established values. In conclusion, the quality control methods for ^99mTc‐ENS are tests on physical properties and pH, radiochemical purity by Whatman‐1 paper/acetone chromatography and cyclohexane extraction and biodistribution studies in rats. The stability of this radiopharmaceutical is at least 6 h at room temperature. Copyright © 2003 John Wiley & Sons, Ltd.     

The effect of sodium valproate on the biochemical parameters of reproductive function in male albino Wistar rats

Objective:

To assess the effects of sodium valproate on intratesticular testosterone and lactic dehydrogenase level in rats.

Methods:

Male Wistar rats (12 weeks old) were treated with sodium valproate and sacrificed at the end of the 2^nd, 4^th, 5^th, 7^th, 10^th and 15^th week, after the last exposure to sodium valproate. The testes were removed, weighed and processed for biochemical analysis.

Results:

The intratesticular testosterone level was significantly (P<0.001) reduced in 200 mg/kg and 400 mg/kg treated rats. The intratesticular lactate dehydrogenase (LDH) level was significantly (P<0.001) increased by valproate in a time dependent manner.

Conclusion:

Valproate causes reversible change in intratesticular testosterone and LDH level.     

Synthesis,radio‐LC–MS analysis and biodistribution in mice of 99mTc–NIM–BAT

S,S′‐bis‐trityl‐N‐BOC‐1,2‐ethylenedicysteamine (S,S′‐bis‐trityl‐N‐BOC–BAT) was conjugated to 2‐nitroimidazole (NIM) through a propylene spacer in order to provide a precursor for a potential technetium‐99 m labelled hypoxia tracer. For labelling with technetium‐99 m, a two‐step one‐pot procedure was developed consisting of deprotection of the ligand by heating in mild acidic conditions and subsequent exchange labelling in the presence of SnCl₂, tartrate and ^99mTcO. The labelling reaction mixture was analyzed using electrospray radio‐LC–MS and the observed mass spectrum corresponding to the main radiometric peak was in accordance with the predicted structure of oxo–Tc(V)–NIM–BAT. ^99mTc–NIM–BAT was purified using RP–HPLC and its biodistribution was evaluated in normal mice at 10 min and 4 h p.i. ^99mTc–NIM–BAT was cleared from plasma mainly by hepatobiliary excretion. Copyright © 2003 John Wiley & Sons, Ltd.     

Efficacy of alternate-day versus everyday dosing of atorvastatin

Background:

Atorvastatin has a longer duration of action than other hydroxymethylglutaryl coenzyme A reductase inhibitors.

Objectives:

The objective was to evaluate the efficacy of alternate day vs. daily dosing of atorvastatin for the treatment of hyperlipidemia.

Materials and Methods:

In this prospective, open label, crossover study, 40 patients with plasma low-density cholesterol (LDL-C) of more than 130 mg/dl and total cholesterol (TC) more than 200 mg/dl were recruited. After baseline tests, they were randomly allocated to two groups. Group A received 20 mg atorvastatin on alternate days and group B received 20 mg atorvastatin daily for 12 weeks. After 4 weeks of washout period, the groups were crossed over to the other treatment regimen for another 12 weeks. Fasting plasma lipid profile and serum alanine transaminase (ALT) and aspartate transaminase (AST) were measured for both groups at 6^th, 12^th, 16^th, 22^nd, and 28^th weeks. Results were pooled across the periods and data between the two groups were compared using unpaired t-test.

Results:

Among the 40 enrolled subjects, 38 completed the study. Both treatment regimens significantly reduced LDL-C and TC compared to baseline. There was no statistically significant difference between the two groups in terms of reduction of plasma LDL-C and TC at 6 and 12 weeks of treatment. Both the regimens were well tolerated.

Conclusion:

Alternate-day treatment with atorvastatin is comparable in efficacy and safety to the established daily treatment regimen, thus being a cost effective alternative.KEY WORDS: Atorvastatin, hyperlipidemia, alternative dosing regimen     

Preparation and biodistribution of novel 99mTc(CO)3‐CNR complexes for myocardial imaging

We evaluated lipophilicity and biodistribution of a series of ^99mTc(CO)₃‐ether isonitrile complexes to determine whether different lipophilicity and structure of isonitrile ligands would improve the imaging properties of the radiopharmaceutical for the heart. Novel ^99mTc(CO)₃‐MIBI analogs were prepared and analyzed by radio‐HPLC, and their lipophilicity was determined. These new complexes could be bi‐ or tri‐substituted in specified pH conditions like ^99mTc(CO)₃‐MIBI. These new complexes exhibited low liver, lungs and blood uptake compared with [^99mTc(CO)₃(MIBI)₃]⁺ though their heart uptake was not so high. Among these complexes, [^99mTc(CO)₃(EPI)₂(OH₂)]⁺ showed higher target to non‐target ratios at 5 and 30 min post‐injection than that of [^99mTc(CO)₃(MIBI)₃]⁺. Copyright © 2007 John Wiley & Sons, Ltd.     

Effect of methylprednisolone on bone mineral density in rats with ovariectomy-induced bone loss and suppressed endogenous adrenaline levels by metyrosine

Objectives:

In this study, effect of methylprednisolone on bone mineral density (BMD) was investigated in rats with overiectomy induced bone lose and suppressed endogenous adrenalin levels, and compared to alendronate.

Materials and Methods:

Severity of bone loss in the examined material (femur bones) was evaluated by BMD measurement.

Results:

The group with the highest BMD value was metyrosinemetyrosine + methylprednisolone combination (0.151 g/cm²), while that with the lowest BMD was methylprednisolone (0.123 g/cm²). Alendronate was effective only when used alone in ovariectomized rats (0.144 g/cm²), but not when used in combination with methylprednisolone (0.124 g/cm²). In the ovariectomized rat group which received only metyrosine, BMD value was statistically indifferent from ovariectomized control group.

Conclusions:

Methylprednisolone protected bone loss in rats with suppressed adrenaline levels because of metyrosinemetyrosine.KEY WORDS: Bone mineral density, bone loss, metirosine, methylprednisolone, ovariectomy, osteoporosis     

Evaluation of a 99mTc‐labelled meso‐bisphenylporphyrin as a tumour image agent

Porphyrins are excellent agents for photodynamic treatment of various types of cancer and also good metal chelators that form highly stable metallo‐complexes with different radionuclides. Therefore, radiolabelled porphyrins could also be potentially used as tumour imaging agents. In this context, the aim of this work was the radiolabelling of meso‐bis[3,4‐bis(carboxymethyleneoxy)phenyl]porphyrin, 2CPP, with Technetium‐99 m (^99mTc) and the evaluation of its radiochemical and biological properties in vitro and in vivo. The labelling procedure was optimized resulting in an efficiency of 92.52 ± 0.48%. The complex ^99mTC‐2CPP remained stable for more than 4 h. The biodistribution showed that ^99mTc‐2CPP is eliminated by gastrointestinal and urinary pathways. The tumour/muscle ratio increases over time, being 3.33 ± 1.22 and 3.55 ± 1.29 in WiDr‐bearing tumours mice and in H1299‐bearing tumours mice, respectively, 6 h post‐injection, showing the tumour specificity of the ^99mTc‐2CPP complex. The favourable tumour/muscle ratio of ^99mTc‐2CPP shows that this complex could potentially be used as tumour imaging agent. Moreover, it could be used to follow the progression or regression of tumours before, during and after the radiotherapy, chemotherapy and photodynamic therapy. Copyright © 2014 John Wiley & Sons, Ltd.     

A comparative study of dalteparin and unfractionated heparin in patients with unstable angina pectoris

Objective:

To compare the efficacy and safety profile of dalteparin, a low-molecular-weight heparin with a standard unfractionated heparin in patients with unstable angina pectoris.

Materials and Methods:

This was a 6-month, prospective, parallel, randomized and open-labeled study. Patients of angina pectoris were randomized to receive either unfractionated heparin or dalteparin for 5 days. They were followed for 21 days during three visits on 1^st, 5^th and 21^st days. A series of resting electrocardiogram were undertaken in all patients on each visit.

Results:

The frequency of the combined clinical outcome of death, myocardial infarction and recurrence of angina was similar during 21 days of follow-up with either dalteparin or intravenous unfractionated heparin. In patients who received dalteparin 2.43% patients developed minor bleeding in the form of epistaxis and 2.5% patients who received unfractionated heparin developed minor bleeding in the form of macroscopic hematuria.

Conclusion:

Dalteparin is as effective and safe as unfractionated heparin in the treatment of unstable angina. Dalteparin does not require routine laboratory monitoring as with unfractionated heparin.KEY WORDS: Anticoagulant, bleeding, low-molecular-weight heparin, unstable angina     

Evaluation of 99mTc‐immunoglobulins for imaging infection in the rat

Three immunoglobulin molecules were evaluated as infection imaging agents in a rat model of S. aureas infection: ^99mTc‐infliximab, ^99mTc‐human immunoglobulin (HIG) and ^99mTc‐rat immunoglobulin (RIG). Infliximab is a chimeric monoclonal antibody specific for human tumour necrosis factor alpha (TNFα). ^99mTc‐HIG was chosen as an exogenous protein and ^99mTc‐RIG as an endogenous marker. Each immunoglobulin was treated with 2‐mercaptoethanol and the reduced antibody was isolated by size exclusion chromatography. In combination with Sn^II‐methylenediphosphonic acid, cold kit formulations were prepared. Native and reduced infliximab were tested for rat TNFα binding ability in vitro. A focal intramuscular infection of S. aureus (1 × 10⁸ colony forming units) was induced in the left thigh muscle of rats, that developed for 24 h. In separate experiments each tracer was administered by intravenous injection, then whole body scintigraphic imaging and biodistribution studies were performed at 1 and 4 h later. ^99mTc‐infliximab, ^99mTc‐HIG and ^99mTc‐RIG were prepared with ?95% radiochemical purity from stable cold kits. Results from the organ assay gave infected (target) to non‐infected (control) muscle ratios for ^99mTc‐infliximab as 5.7±0.8, 7.1±1.2, ^99mTc‐HIG gave 3.1±1.1, 7.8±1.2, and ^99mTc‐RIG 7.9±0.3, 12.5±1.5 at 1 and 4 h, respectively. Infliximab and Sn^II‐infliximab did not bind to rat TNFα by the in vitro assay. Although lacking specific affinity for TNFα, ^99mTc‐infliximab accumulated at infectious sites in vivo. ^99mTc‐infliximab gave similar infection uptake ratios to ^99mTc‐HIG at 1 and 4 h, but these proteins were inferior in comparison to ^99mTc‐RIG, and is likely to be due to increased clearance associated with the foreign protein structure. Copyright © 2006 John Wiley & Sons, Ltd.