Nuclear Medicine and Biology (NUCL MED BIOL)

Publications in this journal

• Article: Application of the Cu-free click reaction in antibody pretargeting

  Sandra M. van den Bosch, Raffaella Rossin, Pascal renart Verkerk, Wolter ten Hoeve, Henk M. Janssen, Johan Lub, Marc S. Robillard
  Nuclear Medicine and Biology 02/2013;
• Article: Efficient synthesis of a fluorine-18 labeled biotin derivative.

  Claesener M, Breyholz HJ, Hermann S, Faust A, Wagner S, Schober O, Schäfers M, Kopka K
  Nuclear Medicine and Biology 09/2012; 39(8):1189-1194.
• Article: Synthesis and characterization of technetium waste forms from an advanced fuel cycle

  Kenneth Czerwinski, Edward mausolf, Frederic Poineau, Dave Kolman, Thomas Hartmann, Phillip Weck, Gordon Jarvinen
  Nuclear Medicine and Biology 01/2010; 37:677.
• Article: Fluorine-18 labeling and biodistribution studies on peroxisome proliferator-activated receptor-gamma ligands: potential positron emission tomography imaging agents.

  Byung Chul Lee, Carmen S Dence, Haibing Zhou, Ephraim E Parent, Michael J Welch, John A Katzenellenbogen
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  ABSTRACT: Peroxisome proliferator-activated receptor-gamma (PPARgamma) is an important regulator of lipid metabolism; it controls the differentiation of preadipocytes and is also found at high levels in small metastatic tumors. In this report, we describe the radiochemical synthesis and evaluation of two (18)F-labeled analogs of the potent and selective PPARgamma agonist farglitazar. The isomeric aromatic fluorine-substituted target compounds [(2S)-(2-benzoylphenylamino)-3-(4-(2-[2-(4-[(18)F]fluorophenyl)-5-methyloxazol-4-yl]ethoxy)-phenyl)propionic acid ([(18)F]-1) and (2S)-[2-(4-fluorobenzoyl)phenylamino]-3-(4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]-phenyl)propionic acid ([(18)F]-2)] were prepared in fluorine-18-labeled form, respectively, by radiofluorination of an iodonium salt precursor or by Ullmann-type condensation with 2-iodo-4'-[(18)F]fluorobenzophenone after nucleophilic aromatic substitution with [(18)F]fluoride ion. Each compound was obtained in high specific activity and good radiochemical yield. (18)F-1 and (18)F-2 have high and selective PPARgamma binding affinities comparable to that of the parent molecule farglitazar, and they were found to have good metabolic stability. Tissue biodistribution studies of (18)F-1 and (18)F-2 were conducted, but PPARgamma-mediated uptake of both agents was minimal. This study completes our first look at an important class of PPARgamma ligands as potential positron emission tomography (PET) imaging agents for breast cancer and vascular disease. Although (18)F-1 and (18)F-2 have high affinities for PPARgamma and good metabolic stability, their poor target-tissue distribution properties, which likely reflect their high lipophilicity combined with the low titer of PPARgamma in target tissues, indicate that they have limited potential as PPARgamma PET imaging agents.
  Nuclear Medicine and Biology 03/2009; 36(2):147-53.
• Article: In vitro and in vivo analysis of [(64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2)]: a site-directed radiopharmaceutical for positron-emission tomography imaging of T-47D human breast cancer tumors.

  Adam F Prasanphanich, Lauren Retzloff, Stephanie R Lane, Prasant K Nanda, Gary L Sieckman, Tammy L Rold, Lixin Ma, Said D Figueroa, Samantha V Sublett, Timothy J Hoffman, Charles J Smith
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  ABSTRACT: Human breast cancer, from which the T-47D cell line was derived, is known to overexpress the gastrin-releasing peptide receptor (GRPR) in some cases. Bombesin (BBN), an agonist for the GRPR, has been appended with a radionuclide capable of positron-emission tomography (PET) imaging and therapy. (64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2) (NO2A=1,4,7-triazacyclononane-1,4-diacetate) has produced high-quality microPET images of GRPR-positive breast cancer xenografted tumors in mice. The imaging probe was synthesized by solid-phase peptide synthesis followed by manual conjugation of the 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) bifunctional chelator and radiolabeling in aqueous solution. The radiolabeled conjugate was subjected to in vitro and in vivo studies to determine its specificity for the GRPR and its pharmacokinetic profile. A T-47D tumor-bearing mouse was imaged with microPET/CT and microMRI imaging. The (64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2) targeting vector was determined to specifically localize in GRPR-positive tissue. Accumulation was observed in the tumor in sufficient quantities to allow for identification of tumors in microPET imaging procedures. For example, uptake and retention in T-47D xenografts at 1, 4 and 24 h were determined to be 2.27+/-0.08, 1.35+/-0.14 and 0.28+/-0.07 % ID/g, respectively. The (64)Cu-NO2A-8-Aoc-BBN(7-14)NH(2) produced high-quality microPET images. The pharmacokinetic profile justifies investigation of this bioconjugate as a potentially useful diagnostic/therapeutic agent. Additionally, the bioconjugate would serve as a good starting point for modification and optimization of similar agents to maximize tumor uptake and minimize nontarget accumulation.
  Nuclear Medicine and Biology 03/2009; 36(2):171-81.
• Source

  Available from: kanazawa-u.ac.jp

  Article: Preparation and evaluation of ethyl [(18)F]fluoroacetate as a proradiotracer of [(18)F]fluoroacetate for the measurement of glial metabolism by PET.

  Tetsuya Mori, Li-Quan Sun, Masato Kobayashi, Yasushi Kiyono, Hidehiko Okazawa, Takako Furukawa, Hidekazu Kawashima, Michael J Welch, Yasuhisa Fujibayashi
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  ABSTRACT: Changes in glial metabolism in brain ischemia, Alzheimer's disease, depression, schizophrenia, epilepsy and manganese neurotoxicity have been reported in recent studies. Therefore, it is very important to measure glial metabolism in vivo for the elucidation and diagnosis of these diseases. Radiolabeled acetate is a good candidate for this purpose, but acetate has little uptake in the brain due to its low lipophilicity. We have designed a new proradiotracer, ethyl [(18)F]fluoroacetate ([(18)F]EFA), which is [(18)F]fluoroacetate ([(18)F]FA) esterified with ethanol, to increase the lipophilicity of fluoroacetate (FA), allowing the measurement of glial metabolism. The synthesis of [(18)F]EFA was achieved using ethyl O-mesyl-glycolate as precursor. The blood-brain barrier permeability of ethyl [1-(14)C]fluoroacetate ([(14)C]EFA) was estimated by a brain uptake index (BUI) method. Hydrolysis of [(14)C]EFA in the brain was calculated by the fraction of radioactivity in lipophilic and water fractions of homogenized brain. Using the plasma of five animal species, the stability of [(14)C]EFA was measured. Biodistribution studies of [(18)F]EFA in ddY mice were carried out and compared with [(18)F]FA. Positron emission tomography (PET) scanning using common marmosets was performed for 90 min postadministration. At 60 min postinjection of [(18)F]EFA, metabolite studies were performed. Organs were dissected from the marmosets, and extracted metabolites were analyzed with a thin-layer chromatography method. The synthesis of [(18)F]EFA was accomplished in a short time (29 min) and with a reproducible radiochemical yield of 28.6+/-3.6% (decay corrected) and a high radiochemical purity of more than 95%. In the brain permeability study, the BUI of [(14)C]EFA was 3.8 times higher than that of sodium [1-(14)C]fluoroacetate. [(14)C]EFA was hydrolyzed rapidly in rat brains. In stability studies using the plasma of five animal species, [(14)C]EFA was stable only in primate plasma. Biodistribution studies in mice showed that the uptake of [(18)F]EFA in selected organs was higher than that of [(18)F]FA. From nonprimate PET studies, [(18)F]EFA was initially taken into the brain after injection. Metabolites related to the tricarboxylic acid (TCA) cycle were detected in common marmoset brain. [(18)F]EFA rapidly enters the brain and is then converted into TCA cycle metabolites in the brains of common marmosets. [(18)F]EFA shows promise as a proradiotracer for the measurement of glial metabolism.
  Nuclear Medicine and Biology 03/2009; 36(2):155-62.
• Article: Tumor targeting and SPECT imaging properties of an (111)In-labeled galectin-3 binding peptide in prostate carcinoma.

  Susan L Deutscher, Said D Figueroa, Senthil R Kumar
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  ABSTRACT: Galectin-3 (gal-3) is a carbohydrate binding protein that has been implicated in cell adhesion, tumor invasion and metastasis. The objective of this study was to evaluate the tumor targeting and imaging properties of a gal-3 binding peptide selected by phage display in a mouse model of metastatic human prostate carcinoma expressing gal-3. A gal-3 binding peptide, ANTPCGPYTHDCPVKR, was synthesized with a Gly-Ser-Gly (GSG) spacer and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) and then radiolabeled with (111)In. The in vitro cell binding properties of (111)In-DOTA-(GSG)-ANTPCGPYTHDCPVKR were determined in metastatic human PC3-M prostate carcinoma cells. The pharmacokinetics and single-photon emission computed tomographic (SPECT/CT) imaging with the radiolabeled peptide were evaluated in SCID mice bearing human PC3-M prostate carcinoma tumor xenografts. The radiolabeled peptide bound with a 50% inhibitory concentration of 191+/-10.2 nM to cultured PC3-M prostate carcinoma cells. In vivo tumor uptake and retention coupled with fast whole-body clearance of the peptide were demonstrated in PC3-M tumor-bearing SCID mice. The tumor uptake rates of the radiolabeled peptide were 1.27+/-0.10%ID/g at 30 min, 0.82+/-0.15%ID/g at 1 h and 0.57+/-0.09%ID/g at 2 h. MicroSPECT/CT studies revealed good tumor uptake of (111)In-DOTA-(GSG)-ANTPCGPYTHDCPVKR 2 h postinjection, while uptake in normal organs was low, with the exception of the kidneys. In vitro cell binding along with tumor uptake of (111)In-DOTA-(GSG)-ANTPCGPYTHDCPVKR in PC3-M human prostate carcinoma tumor-bearing SCID mice suggests the potential of this peptide as a radiopharmaceutical for imaging of gal-3-expressing prostate tumors.
  Nuclear Medicine and Biology 03/2009; 36(2):137-46.
• Article: Synthesis and PET studies of [(11)C-cyano]letrozole (Femara), an aromatase inhibitor drug.

  Kun-Eek Kil, Anat Biegon, Yu-Shin Ding, Andre Fischer, Richard A Ferrieri, Sung Won Kim, Deborah Pareto, Michael J Schueller, Joanna S Fowler
  [show abstract] [hide abstract]
  ABSTRACT: Aromatase, a member of the cytochrome P450 family, converts androgens such as androstenedione and testosterone into estrone and estradiol, respectively. Letrozole (1-[bis-(4-cyanophenyl)methyl]-1H-1,2,4-triazole; Femara) is a high-affinity aromatase inhibitor (K(i)=11.5 nM) that has Food and Drug Administration approval for breast cancer treatment. Here we report the synthesis of carbon-11-labeled letrozole and its assessment as a radiotracer for brain aromatase in the baboon. Letrozole and its precursor (4-[(4-bromophenyl)-1H-1,2,4-triazol-1-ylmethyl]benzonitrile) were prepared in a two-step synthesis from 4-cyanobenzyl bromide and 4-bromobenzyl bromide, respectively. The [(11)C]cyano group was introduced via tetrakis(triphenylphosphine)palladium(0)-catalyzed coupling of [(11)C]cyanide with the bromo precursor. Positron emission tomography (PET) studies in the baboon brain were carried out to assess regional distribution and kinetics, reproducibility of repeated measures and saturability. Log D, the free fraction of letrozole in plasma and the [(11)C-cyano]letrozole fraction in arterial plasma were also measured. [(11)C-cyano]Letrozole was synthesized in 60 min with a radiochemical yield of 79-80%, with a radiochemical purity greater than 98% and a specific activity of 4.16+/-2.21 Ci/mumol at the end of bombardment (n=4). PET studies in the baboon revealed initial rapid and high uptake and initial rapid clearance, followed by slow clearance of carbon-11 from the brain, with no difference between brain regions. Brain kinetics was not affected by coinjection of unlabeled letrozole (0.1 mg/kg). The free fraction of letrozole in plasma was 48.9%, and log D was 1.84. [(11)C-cyano]Letrozole is readily synthesized via a palladium-catalyzed coupling reaction with [(11)C]cyanide. Although it is unsuitable as a PET radiotracer for brain aromatase, as revealed by the absence of regional specificity and saturability in brain regions such as amygdala, which are known to contain aromatase, it may be useful in measuring letrozole distribution and pharmacokinetics in the brain and peripheral organs.
  Nuclear Medicine and Biology 03/2009; 36(2):215-23.
• Article: Development of [(90)Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases.

  Kazuma Ogawa, Hidekazu Kawashima, Kazuhiro Shiba, Kohshin Washiyama, Mitsuyoshi Yoshimoto, Yasushi Kiyono, Masashi Ueda, Hirofumi Mori, Hideo Saji
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  ABSTRACT: Based on the concept of bifunctional radiopharmaceuticals, we have previously developed (186)Re-complex-conjugated bisphosphonate analogs for palliation of painful bone metastases and have demonstrated the utility of these compounds. By applying a similar concept, we hypothesized that a bone-specific directed (90)Y-labeled radiopharmaceutical could be developed. In this study, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as the chelating site, and DOTA was conjugated with 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. [(90)Y]DOTA-complex-conjugated bisphosphonate ([(90)Y]DOTA-HBP) was prepared by coordination with (90)Y, and its biodistribution was studied in comparison to [(90)Y]citrate. In biodistribution experiments, [(90)Y]DOTA-HBP and [(90)Y]citrate rapidly accumulated and resided in the bone. Although [(90)Y]citrate showed a higher level of accumulation in the bone than [(90)Y]DOTA-HBP, the clearances of [(90)Y]DOTA-HBP from the blood and from almost all soft tissues were much faster than those of [(90)Y]citrate. As a result, the estimated absorbed dose ratios of soft tissues to osteogenic cells (target organ) of [(90)Y]DOTA-HBP were lower than those of [(90)Y]citrate. [(90)Y]DOTA-HBP showed superior biodistribution characteristics as a bone-seeking agent and led to a decrease in the level of unnecessary radiation compared to [(90)Y]citrate. Since the DOTA ligand forms a stable complex not only with (90)Y but also with lutetium ((177)Lu), indium ((111)In), gallium ((67/68)Ga), gadolinium (Gd) and so on, complexes of DOTA-conjugated bisphosphonate with various metals could be useful as agents for palliation of metastatic bone pain, bone scintigraphy and magnetic resonance imaging.
  Nuclear Medicine and Biology 03/2009; 36(2):129-35.
• Article: Development and validation of 2-deoxy-2-chloro-d-glucose impurity analysis in [(18)F]FDG by three potential-time waveforms of high-performance liquid chromatography/pulsed amperometric detection.

  Shiou-Shiow Farn, Yuen-Han Yeh, Wuu-Jyh Lin, Lie-Hang Shen
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  ABSTRACT: A suitable three potential-time waveforms for the electrochemical detection of 2-deoxy-2-chloro-d-glucose (ClDG) by gold working electrode and palladium reference electrode have been developed and method validation was performed on Waters 2796 Bioalliance HPLC system coupled with pulsed amperometric detection (HPLC/PAD). FDG and ClDG could be completely separated by 50 mM NaOH mobile phase at a flow rate of 1.0 ml/min; 30 degrees C analytical column temperature; and E1 of 200 mV, T1 of 900 mS; E2 of -770 mV, T2 of 10 mS; E3 of 1400 mV, T3 of 10 mS; acquisition delay (AD) of 300 mS. The validation results were shown as follows: (1) in specificity study, mannose, FDG and ClDG could be completely separated and the retention times of these were 6.2, 11.1 and 13.5 min, respectively, with a total run time of 20 min; (2) the intraday repeatable precision expressed with the CV% in six successive analysis was 0.52% (for FDG) and 0.83% (for ClDG); (3) the interday variability precision expressed with the CV% value of the repeatable precision of 3 days was 0.99%, 0.52% and 0.58% for FDG and 0.71%, 0.83% and 1.24% for ClDG; both the CV% of intraday and interday reproducibilities of FDG and ClDG were better than 1.5%; (4) the accuracy and recovery of FDG and ClDG expressed with the percentage of mean value of three successive analysis were 99.75% (for FDG) and 100.68% (for ClDG) which were all greater than 95%; (5) under optimum conditions, the limit of detection of FDG and ClDG was 0.41 and 0.68 microg/ml, and the limit of quantization of FDG and ClDG was 1.24 and 2.04 microg/ml; (6) the correlation coefficient (r) value of linearity is over 0.999 by 5-50 microg/ml ranges of both compounds, respectively; (7) no interference peak effects by composition of mobile phase or increasing/decreasing flow rate or change of temperature was observed.
  Nuclear Medicine and Biology 03/2009; 36(2):225-31.
• Article: 3'-Deoxy-3'-[(18)F]fluorothymidine (FLT) uptake in breast cancer cells as a measure of proliferation after doxorubicin and docetaxel treatment.

  Helmut Dittmann, Ajnur Jusufoska, Bernhard Matthias Dohmen, Brigitte Smyczek-Gargya, Nikos Fersis, Maren Pritzkow, Rainer Kehlbach, Reinhard Vonthein, Hans Juergen Machulla, Roland Bares
  [show abstract] [hide abstract]
  ABSTRACT: The nucleoside analogue [(18)F]fluorothymidine (FLT) has been designed as a marker of cell proliferation that can be imaged in vivo by positron emission tomography. Clinical pilot studies have demonstrated decreasing FLT uptake following antiproliferative chemotherapy of breast cancer. However, the significance of posttreatment FLT uptake has not been evaluated at the cell level. The aim of this study was to investigate whether FLT uptake detects proliferation inhibition induced by docetaxel or doxorubicin treatment in an in vitro breast cancer model. Breast cancer cells (MCF-7) were treated with docetaxel or doxorubicin for 24 h at drug doses inducing 25-99% inhibition of clonogenic survival (IC(25) to IC(99)). Cellular FLT uptake was estimated at 4 h and at 1, 3 and 5 days interval from chemotherapy. [(3)H]Thymidine incorporation and S-phase fraction were measured for comparison. Analysis of variance and the Bland-Altman difference plot were employed for statistical analysis. After treatment, FLT uptake was declined in dependence of the proliferation inhibition mediated by both chemotherapeutic agents (all P<.0001). The decrease of FLT was greater after doxorubicin treatment than after the corresponding docetaxel dose. With doxorubicin (IC(99)), FLT accumulation was reduced by 70% as early as 4 h after treatment. FLT uptake was closely correlated to [(3)H]thymidine incorporation and S-phase fraction (r=.84 to .93). Right after docetaxel or doxorubicin treatment, FLT uptake corresponds to the reduction of tumor cell proliferation induced. [(18)F]FLT appears promising for monitoring chemosensitivity in breast cancer.
  Nuclear Medicine and Biology 02/2009; 36(2):163-9.
• Source

  Available from: fiocruz.br

  Article: Biodistribution and metabolism of the anti-influenza drug [11C]oseltamivir and its active metabolite [11C]Ro 64-0802 in mice.

  Akiko Hatori, Takuya Arai, Kazuhiko Yanamoto, Tomoteru Yamasaki, Kazunori Kawamura, Joji Yui, Fujiko Konno, Ryuji Nakao, Kazutoshi Suzuki, Ming-Rong Zhang
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  ABSTRACT: Oseltamivir phosphate (Tamiflu) is an orally active anti-influenza drug, which is hydrolyzed by esterase to its carboxylate metabolite Ro 64-0802 with potent activity to inhibit the influenza virus. The abnormal behavior and death associated with the use of oseltamivir have developed into a major problem in Japan where Tamiflu is often prescribed for seasonal influenza. It is critical to determine the amount of oseltamivir and Ro 64-0802 in the human brain and to elucidate the relationship between their amounts and neuropsychiatric side effects. The aim of this study was to evaluate [(11)C]oseltamivir and [(11)C]Ro 64-0802 in mice as promising positron emission tomography (PET) ligands for measuring their amounts in living brains. Whole-body biodistribution of [(11)C]oseltamivir and [(11)C]Ro 64-0802 was determined in mice using the dissection method and micro-PET. In vitro and in vivo metabolite assay was performed in the plasma and brain of mice. Between 1 and 60 min after injection of [(11)C]oseltamivir and [(11)C]Ro 64-0802, 0.20-0.06% and 0.39-0.03% ID/g were detected in the mouse brains, respectively (dissection method). Radioactivity concentrations in the living brains between 0 and 90 min after injection were measured at standardized uptake values of 0.25-0.05 for [(11)C]oseltamivir and 0.38-0.02 for [(11)C]Ro 64-0802 (micro-PET). In vivo metabolite assay demonstrated the presence of [(11)C]oseltamivir and [(11)C]Ro 64-0802 in the brains after [(11)C]oseltamivir injection. This study determined the distribution and metabolism of [(11)C]oseltamivir and [(11)C]Ro 64-0802 in mice. PET could be used to measure their amounts in the living brain and to elucidate the relationship between the amounts in the brain and the side effects of Tamiflu in the central nervous system.
  Nuclear Medicine and Biology 02/2009; 36(1):47-55.
• Article: Evaluating the potential of 188Re-SOCTA-trastuzumab as a new radioimmunoagent for breast cancer treatment.

  Tsai-Yueh Luo, I-Chang Tang, Yu-Long Wu, Kwel-Luen Hsu, Show-Wen Liu, Hong-Chang Kung, Ping-Shan Lai, Wuu-Jyh Lin
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  ABSTRACT: Radioimmunotherapy, which utilizes monoclonal antibodies and therapeutic radioisotopes against antigen-expressing tumor tissues, is an attractive therapeutic approach for cancer therapy. Trastuzumab (Herceptin) is a humanized anti-HER-2/neu monoclonal antibody for breast cancer treatment. In this paper, we introduce a new radioimmunoagent, (188)Re-trastuzumab, via a bifunctional ligand, succinimidyl 3,6-diaza-5-oxo-3-[2-((triphenylmethyl)thio)ethyl]-8-[(triphenylmethyl)thio]octanoate (SOCTA), and evaluate its potential to be a therapeutic radiopharmaceutical for breast cancer treatment. Equimolar amounts of SOCTA and trastuzumab were selected to react, and the conjugation ratio of SOCTA-trastuzumab was evaluated by the MALDI-TOF method. The immunoreactivity of SOCTA-trastuzumab was compared with nonconjugated trastuzumab in HER-2/neu overexpressing human breast cancer cell BT-474. Biodistribution experiment and microSPECT/CT images of (188)Re-SOCTA-trastuzumab being administered intravenously to SCID mice bearing xenografted BT-474 breast cancer were investigated to evaluate the tumor-targeting capability. The covalent attachment of SOCTA to trastuzumab (at 1:1 molar ratio) resulted in the averaged conjugation ratio of 0.27+/-0.06 (n=3). The complex could easily be labeled with (188)Re and achieve 95% radiochemical purity (RCP) after 1 h of reaction at room temperature. The in vitro stability study also revealed that the RCP of (188)Re-SOCTA-trastuzumab was at a value of more than 85% after 48 h of incubation with human serum. The immunoreactivity evaluation showed that SOCTA-trastuzumab and nonconjugated trastuzumab had similar binding capacity (B(max)) to HER-2/neu receptor in BT-474 cells. The animal experiments showed that (188)Re-SOCTA-trastuzumab accumulated more intensively in the tumor site as compared to normal tissue. We suggest that (188)Re-SOCTA-trastuzumab could be a potential candidate for radioimmunotherapy.
  Nuclear Medicine and Biology 02/2009; 36(1):81-8.
• Article: Measurement of glucose metabolism in rat spinal cord slices with dynamic positron autoradiography.

  Xiaoping Fan, Tatsuya Asai, Koichi Morioka, Kenzo Uchida, Hisatoshi Baba, Kuniyoshi Tanaka, Jian Zhuang, Hidehiko Okazawa, Yasuhisa Fujibayashi
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  ABSTRACT: We attempted to measure the regional metabolic rate of glucose (MRglc) in sliced spinal cords in vitro. The thoracic spinal cord of a mature Wister rat was cut into 400-mum slices in oxygenated and cooled (1-4 degrees C) Krebs-Ringer solution. After at least 60 min of preincubation, the spinal cord slices were transferred into double polystyrene chambers and incubated in Krebs-Ringer solution at 36 degrees C, bubbled with 5% O(2)/5% CO(2) gas. To measure MRglc, we used the dynamic positron autoradiography technique (dPAT) with F-18-2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) and the net influx constant of [(18)F]FDG as an index. Uptake curves of [(18)F]FDG were well fitted by straight lines for more than 7 h after the slicing of the spinal cord (linear regression coefficient, r=0.99), indicating a constant uptake of glucose by the spinal cord tissue. The slope (K), which denotes MRglc, is affected by tetrodotoxin, and high K(+) (50 mM) or Ca(2+)-free, high Mg(2+) solution. After 10 min of hypoxia, the K value following reoxygenation was similar to the unloaded control value, but after 45 min of hypoxia, the K value was markedly lower than the unloaded control value, and after >90 min of reoxygenation it was nearly 0. Our results indicate that the living spinal cord slices used retained an activity-dependent metabolism to some extent. This technique may provide a new approach for measuring MRglc in sliced living spinal cord tissue in vitro and for quantifying the dynamic changes in MRglc in response to various interventions such as hypoxia.
  Nuclear Medicine and Biology 02/2009; 36(2):183-9.
• Article: Expressions of glucose transporter Types 1 and 3 and hexokinase-II in diffuse large B-cell lymphoma and other B-cell non-Hodgkin's lymphomas.

  Hye Kyung Shim, Won Woo Lee, So Yeon Park, Haeryoung Kim, Young So, Sang Eun Kim
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  ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) has been reported to show higher uptake of 2-deoxy-2-F18-fluoro-d-glucose (FDG) by positron emission tomography than other B-cell non-Hodgkin's lymphomas (non-DLBCL). The authors addressed the mechanism of FDG uptake in DLBCL by immunostaining for glucose transporter Types 1 (Glut-1) and 3 (Glut-3) and hexokinase-II (HK-II) in excised lymphoma tissues. Sixteen B-cell non-Hodgkin's lymphoma patients (11 DLBCL and 5 non-DLBCL patients) were included in the study because the lymphoma tissues obtained by excision were eligible for immunostaining. The expressions of Glut-1, Glut-3 and HK-II were assessed regarding the percentages of positively stained lymphoma cells (%expression), the staining intensities (none=0, weak=1, moderate=2 and strong=3) and the staining patterns (membranous or cytoplasmic) and compared between DLBCL and non-DLBCL. Glut-1 was not expressed at all in DLBCL or non-DLBCL, and their Glut-3 expressions were not significantly different (P>.05) with respect to %expression (mean+/-S.E.M., 73.6+/-7.3% vs. 72.0+/-3.7%), staining intensity (2.5+/-0.2 vs. 2.6+/-0.2) and staining pattern (membranous pattern dominant; 54.5% vs. 60.0%). However, DLBCL expressed more HK-II than non-DLBCL, i.e., %expression (45.2+/-11.5% vs. 17.0+/-15.8%, P=.0275) and staining intensity (2.3+/-0.2 vs. 0.6+/-0.4, P=.0032). HK-II showed a cytoplasmic location in DLBCL and non-DLBCL. HK-II and Glut-3 contribute significantly to FDG uptake in DLBCL. DLBCL may have higher FDG uptake because it expresses more HK-II, whereas Glut-1 appears to play no role in FDG uptake in B-cell non-Hodgkin's lymphoma.
  Nuclear Medicine and Biology 02/2009; 36(2):191-7.
• Article: Uptake of 99mTc-labeled chondroitin sulfate by chondrocytes and cartilage: a promising agent for imaging of cartilage degeneration?

  Grazyna Sobal, Johannes Menzel, Helmut Sinzinger
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  ABSTRACT: Chondroitin sulfate (CS) is used in the treatment of human osteoarthritis as a slow-acting symptomatic drug. For this reason, we performed uptake studies with (99m)TcCS using different chondrocyte cultures, as well as cartilage tissue in vitro. For uptake studies, adherent monolayer cultures of human chondrocytes (2.7 x 10(4) cells/well) and (99m)TcCS (1 microCi) were used. In parallel, we also performed uptake studies with cell suspensions of human chondrocytes at 1 x 10(6) cells/well incubated with (99m)TcCS (5 microCi) under identical conditions. Uptake was studied also in cartilage tissue samples and frozen tissue sections for autoradiography. The uptake was monitored for 10-240 min, every 10-30 min for cell cultures and for cartilage tissue up to 72 h. As the commercially available drug Condrosulf (IBSA, Lugano, Switzerland) contains magnesium (Mg) stearate as additive, we investigated the uptake with and without this additive. The washout of the tracer was assessed after the uptake experiments with PBS buffer for different time intervals (10 min-3 h). Tracer uptake in monolayer+/-additives with low number of cells was low. With the use of chondrocytes in culture suspensions with higher number of cells, a higher uptake of 5.9+/-0.65% and 1.0+/-0.1% (n=6) was found, with and without additive, respectively. The saturation was achieved after 100 min. With the use of human rib cartilage, the uptake of (99m)TcCS was continuously increasing with time and was very high with additive amounting to 101.8+/-5.2% vs. 53.0+/-8.3% (n=6) without after 72 h and showing delayed saturation up to 30 h. Thus, not only the resorption of the drug is enhanced by Mg-stearate, but also the uptake. The washout of the tracer from cartilage after 3 h of uptake amounted to 3.75+/-1.5% with additive vs. 13.1+/-2.1% without. After 24 h, washout was lower amounting to 1.75+/-0.15% vs. 3.25+/-0.25%, respectively. The autoradiographic studies paralleled the results of in vitro cartilage tissue uptake. These data show that (99m)TcCS accumulates in cartilage tissue, either by acting as a substrate for proteoglycan synthesis or by adsorption to cartilage. (99m)TcCS could therefore be a possible agent to target and radioimage osteoarthritis.
  Nuclear Medicine and Biology 02/2009; 36(1):65-71.
• Article: Synthesis and characterization of [76Br]-labeled high-affinity A3 adenosine receptor ligands for positron emission tomography.

  Dale O Kiesewetter, Lixin Lang, Ying Ma, Abesh Kumar Bhattacharjee, Zhan-Guo Gao, Bhalchandra V Joshi, Artem Melman, Sonia de Castro, Kenneth A Jacobson
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  ABSTRACT: Bromine-76-radiolabeled analogues of previously reported high-affinity A(3) adenosine receptor (A(3)AR) nucleoside ligands have been prepared as potential radiotracers for positron emission tomography. The radiosyntheses were accomplished by oxidative radiobromination on the N(6)-benzyl moiety of trimethyltin precursors. Biodistribution studies of the kinetics of uptake were conducted in awake rats. We prepared an agonist ligand {[(76)Br](1'S,2'R,3'S,4'R,5'S)-4'-{2-chloro-6-[(3-bromophenylmethyl)amino]purin-9-yl}-1'-(methylaminocarbonyl)bicyclo[3.1.0]hexane-2',3'-diol (MRS3581)} in 59% radiochemical yield with a specific activity of 19.5 GBq/micromol and an antagonist ligand {[(76)Br](1'R,2'R,3'S,4'R,5'S)-4'-(6-(3-bromobenzylamino)-2-chloro-9H-purin-9-yl)bicyclo[3.1.0]hexane-2',3'-diol (MRS5147)} in 65% radiochemical yield with a specific activity of 22 GBq/micromol. The resultant products exhibited the expected high affinity (K(i) approximately 0.6 nM) and specific binding at the human A(3)AR in vitro. Biodistribution studies in the rat showed uptake in the organs of excretion and metabolism. The antagonist MRS5147 exhibited increasing uptake in testes, an organ that contains significant quantities of A(3)AR, over a 2-h time course, which suggests the presence of a specific A(3)AR retention mechanism. We were able to compare uptake of the [(76)Br]-labeled antagonist MRS5147 to [(76)Br]agonist MRS3581. The antagonist MRS5147 shows increasing uptake in the testes, an A(3)AR-rich tissue, suggesting that this ligand may have promise as a molecular imaging agent.
  Nuclear Medicine and Biology 02/2009; 36(1):3-10.
• Article: Evaluation of 99mTc(CO)5I as a potential lung perfusion agent.

  Alexander E Miroslavov, Nikolay I Gorshkov, Alexander L Lumpov, Anatoly N Yalfimov, Dmitrii N Suglobov, Beverley L Ellis, Rattana Braddock, Anne-Marie Smith, Mary C Prescott, Richard S Lawson, Harbans L Sharma
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  ABSTRACT: The use of (99m)Tc-macroggregated albumin for lung perfusion imaging is well established in nuclear medicine. However, there have been safety concerns over the use of blood-derived products because of potential contamination by infective agents, for example, Variant Creutzfeldt Jakob Disease. Preliminary work has indicated that Tc(CO)(5)I is primarily taken up in the lungs following intravenous administration. The aim of this study was to evaluate the biodistribution and pharmacokinetics of (99m)Tc(CO)(5)I and its potential as a lung perfusion agent. (99m)Tc(CO)(5)I was synthesized by carbonylation of (99m)TcO(4-) at 160 atm of CO at 170 degrees C in the presence of HI for 40 min. Radiochemical purity was determined by HPLC using (99)Tc(CO)(5)I as a reference. (99m)Tc(CO)(5)I was administered by ear-vein injection to three chinchilla rabbits, and dynamic images were acquired using a gamma camera (Siemens E-cam) over 20 min. Imaging studies were also performed with (99m)Tc-labeled macroaggregated albumin ((99m)Tc-MAA) and (99m)TcO(4-) for comparison. (99m)Tc(CO)(5)I was administered intravenously to Sprague-Dawley rats, and tissue distribution studies were obtained at 15 min and 1 h postinjection. Comparative studies were performed using (99m)Tc-MAA. Radiochemical purity, assessed by HPLC, was 98%. The retention time was similar to that of (99)Tc(CO)(5)I. The dynamic images showed that 70% of (99m)Tc(CO)(5)I appeared promptly in the lungs and remained constant for at least 20 min. In contrast, (99m)TcO(4-) rapidly washed out of the lungs after administration. As expected (99m)Tc-MAA showed 90% lung accumulation. The percentage of injected dose per gram of organ +/-S.D. at 1 h for (99m)Tc(CO)(5)I was as follows: blood, 0.22+/-0.02; lung, 12.8+/-2.87; liver, 0.8+/-0.15; heart, 0.15+/-0.01; kidney, 0.47+/-0.08. The percentage of injected dose per organ +/-S.D. at 1 h was as follows: lung, 22.47+/-2.31; liver, 10.53+/-1.8; heart, 0.18+/-0.01; kidney, 1.2+/-0.17. Tissue distribution studies with (99m)Tc-MAA showed 100% lung uptake. (99m)Tc(CO)(5)I was synthesized with a high radiochemical purity and showed a high accumulation in the lungs. Further work on the mechanism and optimization of lung uptake of (99m)Tc-pentacarbonyl complexes is warranted.
  Nuclear Medicine and Biology 02/2009; 36(1):73-9.