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1.
  • Antoni, Gunnar, et al. (author)
  • Synthesis of l-2,4-Diamino[4-11C]butyric acid and its use in some In vitro and In vivo tumour models
  • 1997
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 24:6, s. 595-601
  • Journal article (peer-reviewed)abstract
    • l-2,4-Diamino[4-11C]butyric acid (DAB) was synthesized by an enzyme catalysed carrier added (0.1 μmol KCN) reaction of hydrogen [11C]cyanide with O-acetyl-l-serine followed by reduction. l-[11C]DAB was obtained with a radiochemical purity higher than 96% and with a decay corrected radiochemical yield of 30–40% within a 32 min reaction time. The enantiomeric excess was 98%. The uptake of l-[11C]DAB was investigated in multicellular aggregates of six different cell lines and animal tumour models. l-[11C]DAB is potentially useful for the assessment of pharmacokinetics of l-DAB in vivo for part of its evaluation as an antitumoural agent, although its use for diagnostic purposes seems limited.
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2.
  • Forngren, B H, et al. (author)
  • Determination of specific radioactivity for Br-76-labeled compounds measuring the ratio between Br-76 and Br-79 using packed capillary liquid chromatography mass spectrometry
  • 2000
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 27:8, s. 851-853
  • Journal article (peer-reviewed)abstract
    • Packed capillary liquid chromatography with electrospray mass spectrometry was used for direct determination of the specific radioactivity by calculation of isotope ratios between the Br-76- and Br-76-labeled analogues of N-((3 aminomethyl)benzyl) 4-bromobenzamide. Using 20 muL injections on packed capillary columns, sufficient mass sensitivity was attained for the determination on an injected amount of radioactivity corresponding to approximately 2 MBq (0.3 pmol of the Br-76 isotopic analogue). NUCL MED BIOL 27;6:851-853, 2000. (C) 2000 Elsevier Science Inc. All rights reserved.
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3.
  • Höglund, Johanna, et al. (author)
  • Optimized indirect (76)Br-bromination of antibodies using N-succinimidyl para-[76Br]bromobenzoate for radioimmuno PET
  • 2000
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 27:8, s. 837-43
  • Journal article (peer-reviewed)abstract
    • Monoclonal antibody 38S1 was radiobrominated with the positron emitter (76)Br (T(1/2) = 16.2 h). Indirect labeling was performed using N-succinimidyl para-(tri-methylstannyl)benzoate (SPMB) as the precursor molecule. SPMB was labeled using Chloramine-T yielding N-succinimidyl para-[(76)Br]bromobenzoate, which was then conjugated to the antibody. Optimization of the labeling conditions and further conjugation gave a total yield ( mean+/-max error) of 49+/-2%. The immunoreactivity of the antibodies was retained after labeling. Thus, antibodies intended for positron emission tomography can be labeled with (76)Br, which gives high yields and preserved immunoreactivity when using the SPMB technique described.
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4.
  • Kälkner, Karl-Mikael, et al. (author)
  • Positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) in patients with metastatic hormone-refractory prostatic adenocarcinoma
  • 1997
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 24:4, s. 319-325
  • Journal article (peer-reviewed)abstract
    • The discovery of neuroendocrine differentiation in hormone-refractory prostatic adenocarcinoma has opened a potentially new therapeutic approach in this group of patients with a poor prognosis and few effective therapy modalities. Based on previous findings of increased uptake of 11C-5-hydroxytryptophan (11C-5-HTP) in neuroendocrine tumours using the PET technique, this tracer was applied in the study of 10 patients with metastatic hormone-refractory prostatic adenocarcinoma. In three patients, the study was repeated after treatment. An increased uptake of 11C-5-HTP was observed in all investigated skeletal lesions, although the magnitude of the uptake was moderate. The difference between the standard uptake values (SUV) in normal bone and metastatic lesions was significant (p < 0.001). A kinetic analysis of the uptake of 11C-5-HTP demonstrates an increase during the first minutes followed by a wash-out and a stabilization of the tissue/blood ratio at about 2. The Patlak plots demonstrated a gradual increase in the transport rate during the first 20 to 30 min, after which a constant level was observed. The SUV varied between patients and between lesions over time and treatment. The uptake of 11C-5-HTP discriminates metastatic lesions from normal bone and may thus aid in the diagnosis and, potentially, in treatment monitoring of metastatic hormone-refractory prostatic adenocarcinoma. Uptake kinetics are characterized by a wash-out and cannot alone be used as proof of neuroendocrine differentiation in hormone-refractory prostatic adenocarcinoma.
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5.
  • Lövqvist, Anna, et al. (author)
  • 76Br-labeled monoclonal anti-CEA antibodies for radioimmuno positron emission tomography
  • 1995
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 22:1, s. 125-131
  • Journal article (peer-reviewed)abstract
    • For the application of anti-tumor monoclonal antibodies (MAbs) in positron emission tomography (PET), labeling radionuclides with half-lives allowing a suitable time frame for imaging are required. The anti-CEA MAb 38S1 was labeled with the positron emitting nuclide 76Br (t1/2 16 h) using bromoperoxidase (BPO), and subsequently affinity purified. A procedure was devised to allow reproducible production of MAb-preparations of high immunoreactivity and with acceptable bromination yield. The biological activity of 76Br-38S1 was retained and comparable to that of chloramine-T labeled 125I-38S1, as tested in vitro.
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6.
  • Mårs, Ulla, et al. (author)
  • Positron emission tomography of experimental melanoma with [76Br]5-bromo-2-thiouracil
  • 2000
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 27:8, s. 845-9
  • Journal article (peer-reviewed)abstract
    • Positron emission tomography (PET) has evolved as a new diagnostic modality in cancer patients. Thioureylenes, such as thiouracil and methimazole, are known to be incorporated into growing melanin and selectively retained in melanotic melanoma. In the present study we used [(76)Br]5-bromo-2-thiouracil as tracer for PET imaging of human and murine melanotic melanoma transplanted subcutaneously into rats. The melanomas were clearly depicted 1 day after the injection, when [(76)Br]5-bromo-2-thiouracil was retained in the tumors though the overall radioactivity concentration in the body had declined. Accumulation of (76)Br was also seen in bladder, liver, and kidney. In addition, the rats were simultaneously injected with [(125)I]5-iodo-2-thiouracil and the tissue distribution of radioactivity was mapped by whole-body autoradiography. The results confirmed the selective uptake of thiouracil in the melanoma where the concentration of (125)I-radioactivity was about three-fold higher than that in the liver and lungs. These results show the possibility of using [(76)Br]5-bromo-2-thiouracil for PET diagnostics of melanoma, including dosimetry, prior to targeted therapy using [(131)I]5-iodo-2-thiouracil or [(211)At]5-astato-2-thiouracil.
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7.
  • Orlova, Anna, et al. (author)
  • Cellular processing of (125)I- and (111)in-labeled epidermal growth factor(EGF) bound to cultured A431 tumor cells
  • 2000
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 27:8, s. 827-35
  • Journal article (peer-reviewed)abstract
    • Low molecular weight of epidermal growth factor (EGF) enables better intratumoral penetration in comparison with larger targeting proteins, but the cellular retention of EGF-associated radioactivity is poor for directly iodinated EGF. An attempt was made to improve intracellular retention by the use of metal-diethylenetriaminepentaacetic acid or nonphenolic linker (N-succinimidyl-para-iodobenzoate) as labeling agents. The use of nonphenolic linker did not improve retention of the radioactivity in A431 carcinoma cell line. The use of the radiometal label provided an appreciable prolongation of radioactivity residence inside the cell.
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8.
  • Orlova, Anna, et al. (author)
  • Cellular processing of 125I- and 111in-labeled epidermal growth factor (EGF) bound to cultured A431 tumor cells
  • 2000
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 27:8, s. 827-835
  • Review (other academic/artistic)abstract
    • Low molecular weight of epidermal growth factor (EGF) enables better intratumoral penetration in comparison with larger targeting proteins, but the cellular retention of EGF-associated radioactivity is poor for directly iodinated EGF. An attempt was made to improve intracellular retention by the use of metal-diethylenetriaminepentaacetic acid or nonphenolic linker (N-succinimidyl-para-iodobenzoate) as labeling agents. The use of nonphenolic linker did not improve retention of the radioactivity in A431 carcinoma cell line. The use of the radiometal label provided an appreciable prolongation of radioactivity residence inside the cell.
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10.
  • Sihver, Wiebke, et al. (author)
  • In vivo positron emission tomography studies on the novel nicotinic receptor agonist [11C]MPA compared with [11C]ABT-418 and (S)(-)[11C]nicotine in rhesus monkeys
  • 1999
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 26:6, s. 633-640
  • Journal article (peer-reviewed)abstract
    • The novel 11C-labeled nicotinic agonist (R,S)-1-[11C]methyl-2(3-pyridyl)azetidine ([11C]MPA) was evaluated as a positron emission tomography (PET) ligand for in vivo characterization of nicotinic acetylcholine receptors in the brain of Rhesus monkeys in comparison with the nicotinic ligands (S)-3-methyl-5-(1-[11C]methyl-2-pyrrolidinyl)isoxazol ([11C]ABT-418) and (S)(-)[11C]nicotine. The nicotinic receptor agonist [11C]MPA demonstrated rapid uptake into the brain to a similar extent as (S)(-) [11C]nicotine and [11C]ABT-418. When unlabeled (S)(-)nicotine (0.02 mg/kg) was administered 5 min before the radioactive tracers, the uptake of [11C]MPA was decreased by 25% in the thalamus, 19% in the temporal cortex, and 11% in the cerebellum, whereas an increase was found for the uptake of (S)(-)[11C]nicotine and [11C]ABT-418. This finding indicates specific binding of [11C]MPA to nicotinic receptors in the brain in a simple classical displacement study. [11C]MPA seems to be a more promising radiotracer than (S)(-)[11C]nicotine or [11C]ABT-418 for PET studies to characterize nicotinic receptors in the brain.
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11.
  • Sundberg, Åsa Liljegren, et al. (author)
  • Cellular retention of radioactivity and increased radiation dose : Modelexperiments with EGF-dextran
  • 2003
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 30:3, s. 303-315
  • Journal article (peer-reviewed)abstract
    • Targeting of tumor cells with radiolabeled biomolecules is a possible approach to inactivate disseminated tumor cells. However, rapid degradation of the biomolecules after cellular internalization and subsequent excretion of the radioactivity is a problem. We studied the possibility of using dextran as a carrier of radionuclides to improve the intracellular retention. An EGF-dextran conjugate, aimed for targeting of tumor cells overexpressing the EGF-receptor, was used as model. Retention tests were performed with (125)I on different parts: [(125)I]-EGF-dextran-[(125)I], [(125)I]-EGF-dextran and EGF-dextran-[(125)I]. Comparisons were made with [(125)I]-EGF. The radiolabeled compounds were incubated with cultured glioma cells for different times. The cellular retention of radioactivity was then measured for up to 24 h. Expected radiation doses at the cellular level were calculated assuming that (131)I, instead of (125)I, was coupled to EGF and EGF-dextran. The results indicated that the EGF-part of the conjugate was degraded and the EGF-attached radioactivity was rapidly excreted, whereas radioactivity on dextran was retained intracellularly to a high degree, i.e. 70-80% of the radioactivity bound to dextran was still cell-associated after 24 h. The retention after 24 h was significantly higher (p < 0.001) when the radioactivity was on the dextran instead of the EGF-part. The radiolabeled EGF-dextran had a notably high specific radioactivity; up to 11 MBq/microg. There was potential for at least hundred times increased radiation dose per receptor interaction when the radioactivity was on the dextran part. The advantage with radioactivity on the dextran part was the high cellular retention and the high specific radioactivity (higher than previously reported for other residualizing labels) without severe loss of receptor specific binding. Thus, dextran seems suitable as a carrier of radionuclides aimed for therapy and gives potential for a highly increased radiation dose.
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13.
  • Sundin, Johanna, et al. (author)
  • High yield direct 76Br-bromination of monoclonal antibodies using Cloramine-T
  • 1999
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 26:8, s. 923-929
  • Journal article (peer-reviewed)abstract
    • Monoclonal antibody (MAb) A33 was labeled with the positron emitter 76Br (T(1/2) = 16.2 h). Direct labeling was done using the conventional chloramine-T method. After optimization of the labeling conditions, a maximum yield (mean +/- max error) of 77 +/- 2% was obtained at pH 6.8. In vitro binding of 76Br-A33 to SW1222 colonic cancer cells showed that the immunoreactivity was retained. Also, the MAbs 38S1 and 3S193 and the peptide hEGF were 76Br-labeled, resulting in labeling yields (mean +/- max error) of 75 +/- 3%, 63 +/- 4%, and 73 +/- 0.1%, respectively. We conclude that antibodies and peptides can be labeled conveniently with 76Br for the purpose of whole-body tumour imaging by positron emission tomography.
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14.
  • Tolmachev, Vladimir, et al. (author)
  • 114mIn, a candidate for radionuclide therapy : low-energy cyclotron production and labeling of DTPA-D-phe-octreotide
  • 2000
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 27:2, s. 183-188
  • Journal article (peer-reviewed)abstract
    • A method for production of carrier-free (114m)In (half-life 49.5 days), which is a potential radionuclide for radionuclide therapy of slowly growing tumors, is presented. A target consisting of five enriched cadmium ((114)Cd) foils, each 50 microm thick, was irradiated by protons (from 12.6-6.5 MeV) giving a target yield of 0. 8 MBq/microAh. A simple and cost-efficient thermal diffusion method was used for the separation. The irradiated target foils were heated for 2 h at 306 degrees C and then etched in 0.05 M HCl. The obtained cadmium/indium solution was purified using a cation ion-exchange resin (AG 1 x 8, Bio-Rad Laboratories, Hercules, CA USA). An overall yield of approximately 60% was obtained, whereas the loss of the target material was <1% per separation cycle. The (114m)In production gave (114m)In with high specific radioactivity and was successfully used to label diethylenetriamine pentaacetic acid (DTPA)-D-Phe-octreotide. Furthermore, no difference in biodistribution between [(114m)In]- and [(111)In]-DTPA-D-Phe(1)-octreotide in tumor-bearing nude mice was seen. The high radionuclide uptake in the tumors indicates a good receptor binding of the labeled octreotide.
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15.
  • Westerberg, Göran, et al. (author)
  • Labelling of polysaccharides using [11C]cyanogen bromide : In vivo and in vitro evaluation of 11C-hyaluronan uptake kinetics
  • 1995
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 22:2, s. 251-256
  • Journal article (peer-reviewed)abstract
    • A method for the 11C-labelling of polysaccharides in high specific radioactivity is described. Dextran and hyaluronan were treated with [11C]cyanogen bromide in aqueous solution at pH 11.5 to give 30-47% radiochemical yields with higher than 98% radiochemical purity in synthesis times of 24-26 min counted from the end of bombardment. Specific radioactivities at the end of synthesis ranged from 0.12 to 3.1 Ci/mumol. The biodistribution kinetics of [11C]hyaluronan injected intravenously was studied in rats by means of positron emission tomography, showing a rapid and displaceable uptake in liver. Uptake and displacement of [11C]hyaluronan was also demonstrated in cultured rat liver endothelial cells.
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16.
  • Örlefors, Håkan, et al. (author)
  • Demonstration of high monoamineoxidase-A levels in neuroendocrine gastroenteropancreatic tumors in vitro and in vivo : tumor visualization using positron emission tomography with 11C-harmine
  • 2003
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 30:6, s. 669-679
  • Journal article (peer-reviewed)abstract
    • Background and Aims: A majority of neuroendocrine gastroenteropancreatic (GEP) tumors can be detected by conventional radiological methods and scintigraphic techniques. Still there are problems to visualize small tumor lesions and non-functioning tumors. The aim of this study was to investigate some of the monoamine processing pathways of neuroendocrine GEP-tumors and try to find a new tracer substance for in vivo characterization and visualization by Positron Emission Tomography (PET). Subjects and Methods: Autoradiography of tumor sections from 8 midgut carcinoids (MGC) and 8 endocrine pancreatic tumors (EPT) was performed with C-11-labeled tracers for serotonin and dopamine transporters, serotonin HT2A-, dopamine D1- and muscarinic receptors and for monoamine oxidase A (MAO-A). The in vitro results initiated PET studies with C-11-Harmine in 4 patients with MGC and 7 patients with EPT (one insulinoma, two glucagonomas and four non-functioning EPT). Results: The MAO-A-ligand Harmine expressed specific in vitro binding of 87 +/- 21% for MGC and 125 +/- 50% for EPT, compared to reference tissue (rat brain, 100%). All other substances showed relatively low specific binding. C-11-harmine-PET could visualize tumors in all patients. The mean standardized uptake value (SUV) for MGC was 7.5 +/- 3.9 and for EPT 12.9 +/- 2.7, whereas the SUV of normal liver, intestine and pancreas were 3.1 +/- 0.5, 3.4 +/- 1.2 and 8.9 +/- 3.0 respectively. Conclusions: This study demonstrates in vitro and in vivo that neuroendocrine GEP-tumors are characterized by a high MAO-A-expression, thereby adding to the similarities of neuronal and neuroendocrine tissue. It also indicates a possible application for C-11-harmine as a new PET-tracer for neuroendocrine GEP-tumors with the potential to visualize also non-functioning EPT's.
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17.
  • Ahlgren, Sara, et al. (author)
  • Kit formulation for 99mTc-labeling of recombinant anti-HER2 Affibody molecules with a C-terminally engineered cysteine
  • 2010
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 37:5, s. 539-546
  • Journal article (peer-reviewed)abstract
    • Introduction: Molecular imaging of HER2-expression in malignant tumors provides potentially important information for patient management. Affibody molecules have shown to be suitable tracers for imaging applications using SPECT or PET. Results from an earlier evaluation of the application of site specific 99mTc-labeling on the Affibody molecule, ZHER2:2395-C, were favorable. Methods: As a preparation for clinical application of this tracer we have developed and evaluated a robust single-vial freeze-dried kit, allowing labeling of the Affibody molecule, ZHER2:2395-C, with 99mTc. Results: The composition of the kit (containing glucoheptonate, EDTA and tin(II)-chloride), as well as the protein amount and the pertechnetate volume were optimized for a high labeling yield (> 90 %) and minimal presence of reduced hydrolyzed technetium colloids (< 1 %). The specificity to HER2 receptors, the binding competence and the stability in PBS and murine serum were verified in vitro. The shelf-life was also evaluated in vitro, showing no reduction in labeling yield or binding capacity to HER2-expressing cells after over 400 days of storage of the single-vial freeze-dried kit. Conclusions: ZHER2:2395-C labeled with 99mTc using the lyophilized kit was stable and resulted in a favorable biodistribution in an in vivo evaluation in normal NMRI mice.
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19.
  • Almqvist, Ylva, et al. (author)
  • In vitro and in vivo characterization of 177Lu‑huA33 : A radioimmunoconjugate against colorectal cancer
  • 2006
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 33:8, s. 991-998
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION: The humanized monoclonal antibody A33 (huA33) is a potential targeting agent against colorectal carcinoma since the A33 antigen is highly and homogenously expressed in >95% of all colorectal cancers, both primary tumors and metastases. The aim of this study was to determine the biodistribution and tumor-targeting ability of (177)Lu-labeled huA33. METHODS: huA33 was labeled with the beta-emitting therapeutic nuclide (177)Lu using the chelator CHX-A"-DTPA, and the properties of the (177)Lu-CHX-A"-huA33 ((177)Lu-huA33) conjugate was determined both in vitro and in vivo in a biodistribution study in nude mice xenografted with colorectal SW1222 tumor cells. RESULTS: The (177)Lu-huA33 conjugate bound specifically to colorectal cancer cells in vitro (with a K(D) value of 2.3+/-0.3 nM, determined by a saturation assay) and in vivo. The tumor uptake of (177)Lu-huA33 was very high, peaking at 134+/-21%ID/g 72 h postinjection (pi). Normal tissue uptake was low; radioactivity concentration in blood (which had the second highest radioactivity concentration) was lower than in tumor at all time points studied (8 h to 10 days). The tumor-to-blood ratio increased with time, reaching 70+/-30, 10 days pi. Throughout the study, the uptake of (177)Lu in bone (known to accumulate free (177)Lu) was low, and the fraction of protein-bound (177)Lu in plasma samples was high (95% to 99%). This indicates high stability of the (177)Lu-huA33 conjugate in vivo. CONCLUSION: The (177)Lu-huA33 conjugate shows a very favorable biodistribution, with an impressively high tumor uptake and high tumor-to-organ ratios, indicating that the conjugate may be suitable for radioimmunotherapy of colorectal cancer.
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20.
  • Altai, Mohamed, et al. (author)
  • Evaluation of affibody molecule-based PNA-mediated radionuclide pretargeting : Development of an optimized conjugation protocol and 177Lu labeling
  • 2017
  • In: Nuclear Medicine and Biology. - : Elsevier. - 0969-8051 .- 1872-9614. ; 54, s. 1-9
  • Journal article (peer-reviewed)abstract
    • Introduction We have previously developed a pretargeting approach for affibody-mediated cancer therapy based on PNA–PNA hybridization. In this article we have further developed this approach by optimizing the production of the primary agent, ZHER2:342-SR-HP1, and labeling the secondary agent, HP2, with the therapeutic radionuclide 177Lu. We also studied the biodistribution profile of 177Lu-HP2 in mice, and evaluated pretargeting with 177Lu-HP2 in vitro and in vivo. Methods The biodistribution profile of 177Lu-HP2 was evaluated in NMRI mice and compared to the previously studied 111In-HP2. Pretargeting using 177Lu-HP2 was studied in vitro using the HER2-expressing cell lines BT‐474 and SKOV-3, and in vivo in mice bearing SKOV-3 xenografts. Results and conclusion Using an optimized production protocol for ZHER2:342-SR-HP1 the ligation time was reduced from 15 h to 30 min, and the yield increased from 45% to 70%. 177Lu-labeled HP2 binds specifically in vitro to BT474 and SKOV-3 cells pre-treated with ZHER2:342-SR-HP1. 177Lu-HP2 was shown to have a more rapid blood clearance compared to 111In-HP2 in NMRI mice, and the measured radioactivity in blood was 0.22 ± 0.1 and 0.68 ± 0.07%ID/g for 177Lu- and 111In-HP2, respectively, at 1 h p.i. In contrast, no significant difference in kidney uptake was observed (4.47 ± 1.17 and 3.94 ± 0.58%ID/g for 177Lu- and 111In-HP2, respectively, at 1 h p.i.). Co-injection with either Gelofusine or lysine significantly reduced the kidney uptake for 177Lu-HP2 (1.0 ± 0.1 and 1.6 ± 0.2, respectively, vs. 2.97 ± 0.87%ID/g in controls at 4 h p.i.). 177Lu-HP2 accumulated in SKOV-3 xenografts in BALB/C nu/nu mice when administered after injection of ZHER2:342-SR-HP1. Without pre-injection of ZHER2:342-SR-HP1, the uptake of 177Lu-HP2 was about 90-fold lower in tumor (0.23 ± 0.08 vs. 20.7 ± 3.5%ID/g). The tumor-to-kidney radioactivity accumulation ratio was almost 5-fold higher in the group of mice pre-injected with ZHER2:342-SR-HP1. In conclusion, 177Lu-HP2 was shown to be a promising secondary agent for affibody-mediated tumor pretargeting in vivo.
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21.
  • Altai, Mohamed, et al. (author)
  • Preclinical evaluation of anti-HER2 Affibody molecules site-specifically labeled with In-111 using a maleimido derivative of NODAGA
  • 2012
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 39:4, s. 518-529
  • Journal article (peer-reviewed)abstract
    • Introduction: Affibody molecules have demonstrated potential for radionuclide molecular imaging. The aim of this study was to synthesize and evaluate a maleimido derivative of the 1,4,7-triazacyclononane-l-glutaric acid-4,7-diacetic acid (NODAGA) for site-specific labeling of anti-HER2 Affibody molecule. Methods: The maleimidoethylmonoamide NODAGA (MMA-NODAGA) was synthesized and conjugated to Z(HER2:2395) Affibody molecule having a C-terminal cysteine. Labeling efficiency, binding specificity to and cell internalization by HER2-expressing cells of [In-111-MMA-NODAGA-Cys(61)]-Z(HER2:2395) were studied. Biodistribution of [In-111-MMA-NODAGA-Cys(61)]-Z(HER2:2395) and [In-111-MMA-DOTA-Cys(61)]-Z(HER2:2395) was compared in mice. Results: The affinity of [MMA-NODAGA-Cys(61)]-Z(HER2:2395) binding to HER2 was 67 pM. The In-1111-labeling yield was 99.6%+/- 0.5% after 30 min at 60 degrees C. [In-111-MMA-NODAGA-Cys(61)]-Z(HER2:2395) bound specifically to HER2-expressing cells in vitro and in vivo. Tumor uptake of [In-111-MMA-NODAGA-Cys(61)]-ZHER(2:2395) in mice bearing DU-145 xenografts (4.7%+/- 0.8% ID/g) was lower than uptake of [In-111-MMA-DOTA-Cys(61)]-Z(HER2:2395) (7.5%+/- 1.6% ID/g). However, tumor-to-organ ratios were higher for [In-111-MMA-NODAGA-Cys(61)]-Z(HER2:2395) due to higher clearance rate from normal tissues. Conclusions: MMA-NODAGA is a promising chelator for site-specific labeling of targeting proteins containing unpaired cysteine. Appreciable influence of chelators on targeting properties of Affibody molecules was demonstrated.
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24.
  • Bergström, Mats, et al. (author)
  • Modulation of organ uptake of 11C-labelled L-DOPA
  • 1997
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 24:1, s. 15-19
  • Journal article (peer-reviewed)abstract
    • The present study was undertaken to investigate if pretreatment with pharmacological agents could change the organ uptake of 11C-labelled L-DOPA, and especially if the urinary excretion could be decreased. L-[beta-11C]DOPA was injected IV into unanesthetized Sprague-Dawley rats. After 20 min the rats were decapitated and organs taken out for radioactivity measurements. The uptake in the organs was investigated in animals only given the tracer, and in animals pretreated with drugs such as decarboxylase inhibitors carbidopa and benserazide as well as the monoamine oxidase inhibitors deprenyl, clorgyline, and the COMT inhibitor OR-486. A marked decrease in the urinary radioactivity was observed after carbidopa and benserazide administration. HPLC analysis revealed that under native conditions the major part of urinary radioactivity existed as dopamine, which was eliminated by the decarboxylase inhibitors. After pretreatment with the COMT inhibitor OR-486, the radioactivity uptake in the pancreas increased fourfold as compared to non-treated animals. HPLC analysis showed that this correlated with a marked increase in radiolabelled DOPAC. In the other organs and with the other drugs, only small effects were observed. With L-[beta-11C]fluoroDOPA as a tracer, similar results were observed although the increase in the pancreas by OR-486 had a lower magnitude. These studies suggest that it might be possible to improve the diagnostic ratio of L-[beta-11C]DOPA or L-[18F]fluoroDOPA in whole-body PET studies by pretreating the patient with decarboxylase inhibitor for reducing the urinary excretion and potentially increase the target organ uptake by COMT inhibition.
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25.
  • Bruskin, Alexander, et al. (author)
  • Radiobromination of monoclonal antibody using potassium [76Br] (4 isothiocyanatobenzyl-ammonio)-bromo-decahydro-closo-dodecaborate (Bromo-DABI)
  • 2004
  • In: Nuclear Medicine and Biology. - 0969-8051 .- 1872-9614. ; 31:2, s. 205-11
  • Journal article (peer-reviewed)abstract
    • The use of charged linkers in attaching radiohalogens to tumor-seeking biomolecules may improve intracellular retention of the radioactive label after internalization and degradation of targeting proteins. Derivatives of polyhedral boron clusters, such as closo-dodecaborate (2-) anion, might be possible charged linkers. In this study, a bifunctional derivative of closo-dodecaborate, (4-isothiocyanatobenzyl-ammonio)-undecahydro-closo-dodecaborate (DABI) was labeled with positron-emitting nuclide (76)Br (T 1/2 = 16.2 h) and coupled to anti-HER2/neu humanized antibody Trastuzumab. The overall labeling yield at optimized conditions was 80.7 +/- 0.6%. The label was proven to be stable in vitro in physiological and a set of denaturing conditions. The labeled antibody retained its capacity to bind to HER-2/neu antigen expressing cells. The results of the study demonstrated feasibility for using derivatives of closo-dodecaborate in indirect labeling of antibodies for radioimmunoPET.
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26.
  • Coenen, Heinz H., et al. (author)
  • Consensus nomenclature rules for radiopharmaceutical chemistry - Setting the record straight
  • 2017
  • In: Nuclear Medicine and Biology. - : ELSEVIER SCIENCE INC. - 0969-8051 .- 1872-9614. ; 55, s. V-XI
  • Journal article (peer-reviewed)abstract
    • Over recent years, within the community of radiopharmaceutical sciences, there has been an increased incidence of incorrect usage of established scientific terms and conventions, and even the emergence of 'self-invented' terms. In order to address these concerns, an international Working Group on 'Nomenclature in Radiopharmaceutical Chemistry and related areas' was established in 2015 to achieve clarification of terms and to generate consensus on the utilisation of a standardised nomenclature pertinent to the field. Upon open consultation, the following consensus guidelines were agreed, which aim to: Provide a reference source for nomenclature good practice in the radiopharmaceutical sciences. Clarify the use of terms and rules concerning exclusively radiopharmaceutical terminology, i.e. nuclear-and radiochemical terms, symbols and expressions. Address gaps and inconsistencies in existing radiochemistry nomenclature rules. Provide source literature for further harmonisation beyond our immediate peer group (publishers, editors, IUPAC, pharmacopoeias, etc.).
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27.
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28.
  • Davoodpour, Padideh, et al. (author)
  • Effects of 2-methoxyestradiol on proliferation, apoptosis and PET-tracer uptake in human prostate cancer cell aggregates
  • 2004
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 31:7, s. 867-874
  • Journal article (peer-reviewed)abstract
    • The purpose of this study was to investigate the potential use of PET in vivo to record cytotoxic effects of 2-methoxyestradiol (2-ME), an endogenous metabolite of 17beta-estradiol. The anti-proliferative and pro-apoptotic effects of 2-ME on human prostate cancer cell (PC3) aggregates in vitro, were correlated with the uptake of fluoro-deoxy-D-glucose, FMAU and choline labelled with 18F, 11C, or 3H. 2-ME clearly reduced growth of PC3 aggregates and induced apoptosis in a dose-dependent manner. However, the uptake of the putative proliferation markers 11C-FMAU or 3H-choline failed to record the growth inhibitory effects of 2-ME on PC3 cell aggregates. The uptake of 18F-FDG was used as a marker for effects on cellular metabolism and also failed to show any dose-dependent effects in PC3 aggregates. The use of these PET-tracers in vivo is therefore not recommended in order to evaluate the cytotoxic effects of 2-ME on human prostate cancer cells.
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29.
  • Edwards, David, et al. (author)
  • The biodistribution of NC100668 and the effect of excess NC100668 on the biodistribution and kidney retention of Tc-99m-NC100668 in the rat
  • 2007
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 34:3, s. 315-323
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION: (99m)Tc-NC100668 is being developed to aid the diagnosis of thromboemboli. The purpose of this study was to investigate if the presence of excess NC100668 interferes with the biodistribution and blood clot uptake of (99m)Tc-NC100668. The secondary aim was to investigate the causes underlying the kidney retention of (99m)Tc-NC100668. METHODS: The uptake of a (14)C-labelled analogue of NC100668, as well as (99m)Tc-NC100668, into plasma (in vitro) and blood (in vivo) clots was determined. The biodistribution of (99m)Tc-NC100668 at a range of NC100668 doses was studied in normal Wistar rats and those bearing experimentally induced deep venous thrombosis. The biodistribution of a negative control peptide and (99m)Tc-NC100668 plus L-lysine was studied in healthy male Wistar rats. RESULTS: The biodistribution as well as plasma clot uptake of [Asn-U-(14)C]NC100668 and (99m)Tc-NC100668 was similar. Apart from some reduction in kidney retention, the biodistribution and uptake of radioactivity into the blood clot were not significantly affected by the presence of up to 1000 times the clinical dose of NC100668. Kidney retention of radioactivity could be more effectively reduced by coadministration of 889 microg/kg NC100668 than 450 mg/kg L-lysine. A negative control peptide with no affinity for FXIIIa demonstrated very little kidney retention. CONCLUSIONS: The biodistribution and blood clot uptake of (99m)Tc-NC100668 and [Asn-U-(14)C]NC100668 are similar. With the exception of the kidneys, (99m)Tc-NC100668 biodistribution and blood clot uptake are unaffected by the presence of unlabelled NC100668. The kidney retention of radioactivity is probably due to transglutaminase activity and, to a lesser extent, nonspecific charge-mediated endocytosis.
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30.
  • Eriksson, Jonas, et al. (author)
  • Synthesis and preclinical evaluation of the CRTH2 antagonist [11C]MK-7246 as a novel PET tracer and potential surrogate marker for pancreatic beta-cell mass
  • 2019
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 71, s. 1-10
  • Journal article (peer-reviewed)abstract
    • Introduction: MK-7246 is a potent and selective antagonist for chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Within the pancreas CRTH2 is selectively expressed in pancreatic β-cells where it is believed to play a role in insulin release. Reduction in β-cell mass and insufficient insulin secretion in response to elevated blood glucose levels is a hallmark for type 1 and type 2 diabetes. Reported here is the synthesis of [11C]MK-7246 and initial preclinical evaluation towards CRTH2 imaging. The aim is to develop a method to quantify β-cell mass with PET and facilitate non-invasive studies of disease progression in individuals with type 2 diabetes.Methods: The precursor N-desmethyl-O-methyl MK-7246 was synthesized in seven steps and subjected to methylation with [11C]methyl iodide followed by hydrolysis to obtain [11C]MK-7246 labelled in the N-methyl position. Preclinical evaluation included in vitro radiography and immune-staining performed in human pancreatic biopsies. Biodistribution studies were performed in rat by PET-MRI and in pig by PET-CT imaging. The specific tracer uptake was examined in pig by scanning before and after administration of MK-7246 (1 mg/kg). Predicted dosimetry of [11C]MK-7246 in human males was estimated based on the biodistribution in rat.Results: [11C]MK-7246 was obtained with activities sufficient for the current investigations (270±120 MBq) and a radiochemical purity of 93±2%. The tracer displayed focal binding in areas with insulin positive islet of Langerhans in human pancreas sections. Baseline uptake in pig was significantly reduced in CRTH2-rich areas after administration of MK-7246; pancreas (66% reduction) and spleen (88% reduction). [11C]MK-7246 exhibited a safe human predicted dosimetry profile as extrapolated from the rat biodistribution data.Conclusions: Initial preclinical in vitro and in vivo evaluation of [11C]MK-7246 show binding and biodistribution properties suitable for PET imaging of CRTH2. Further studies are warranted to assess its potential in β-cell mass imaging and CRTH2 drug development.
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31.
  • Eriksson, Jonas, et al. (author)
  • The development of 11C-carbonylation chemistry : A systematic view
  • 2021
  • In: Nuclear Medicine and Biology. - : Elsevier. - 0969-8051 .- 1872-9614. ; 92, s. 115-137
  • Research review (peer-reviewed)abstract
    • The prospects for using carbon-11 labelled compounds in molecular imaging has improved with the development of diverse synthesis methods, including C-11-carbonylations and refined techniques to handle [C-11]carbon monoxide at a nanomole scale. Facilitating biological research and molecular imaging was the driving force when [C-11]carbon monoxide was used in the first in vivo application with carbon-11 in human (1945) and when [C-11]carbon monoxide was used for the first time as a chemical reagent in the synthesis of [C-11]phosgene (1978). This review examines a rich plethora of labelled compounds synthesized from [C-11]carbon monoxide, their chemistry and use in molecular imaging. While the strong development of the C-11-carbonylation chemistry has expanded the carbon-11 domain considerably, it could be argued that the number of C-11-carbonyl compounds entering biological investigations should be higher. The reason for this may partly be the lack of commercially available synthesis instruments designed for C-11-carbonylations. But as this review shows, novel and greatly simplified methods to handle [C-11]carbon monoxide have been developed. The next important challenge is to make full use of these technologies and synthesis methods in PET research. When there is a PET-tracer that meets a more general need, the incentive to implement C-11-carbonylation protocols will increase.
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32.
  • Eriksson, Olof, et al. (author)
  • 5-Fluoro-[beta-C-11]-L-tryptophan is a functional analogue of 5-hydroxy-[beta-C-11]-L-tryptophan in vitro but not in vivo
  • 2013
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 40:4, s. 567-575
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION: 5-Hydroxy-[β-(11)C]-L-tryptophan ([(11)C]HTP) is an established positron emission tomography (PET) imaging agent for neuroendocrine tumors (NETs). It has also been used for other clinical research purposes in neurology and diabetes. However, its widespread use is limited by the short physical half-life of the radionuclide and a difficult radiosynthesis. Therefore, a Fluorine-18 labeled analogue, 5-[(18)F]Fluoro-L-tryptophan ([(18)F]FTRP), has been proposed as a functional analogue. There is no published method for the synthesis of L-[(18)F]FTRP. We have therefore developed a synthesis of 5-fluoro-[β-(11)C]-L-tryptophan ([(11)C]FTRP), based on the existing chemo-enzymatic method for [(11)C]HTP and evaluated the potential usefulness of radiolabeled FTRP as a substitute for [(11)C]HTP.METHODS: The in vitro and in vivo behavior of [(11)C]FTRP, including the dependence of key enzymes in the serotonergic metabolic pathway, was investigated in NET cell lines, NET xenograft carrying immunodeficient mice, normal rats and in non-human primate. [(11)C]HTP was used for direct comparison.RESULTS: Uptake of [(11)C]FTRP in NET cell lines in vitro was mediated by enzymes involved in serotonin synthesis and metabolism, similar to [(11)C]HTP. In vivo biodistribution, either in rodent or non-human primate, was not affected by selectively inhibiting enzymatic steps in the serotonergic metabolic pathway.CONCLUSION: [(11)C]FTRP has in vitro biological function similar to that of [(11)C]HTP. However, this function is not retained in vivo as shown by biodistribution and PET/CT studies. Radiolabeled FTRP is thus not likely to provide an advantage over [(11)C]HTP in PET imaging in oncology, neurology or diabetes.
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33.
  • Eriksson, Olof, et al. (author)
  • Distribution of adoptively transferred porcine T-lymphoblasts tracked by (18)F-2-fluoro-2-deoxy-D-glucose and position emission tomography
  • 2011
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 38:6, s. 827-833
  • Journal article (peer-reviewed)abstract
    • Introduction: Autologous or allogeneic transfer of tumor-infiltrating T-Iymphocytes is a promising treatment for metastatic cancers, but a major concern is the difficulty in evaluating cell trafficking and distribution in adoptive cell therapy. This study presents a method of tracking transfusion of T-Iymphoblasts in a porcine model by (18)F-2-fluoro-2-deoxy-D-glucose ([(18)F]FDG) and positron emission tomography. Methods: T-Iymphoblasts were labeled with the positron-emitting tracer [(18)F]FDG through incubation. The T-Iymphoblasts were administered into the bloodstream, and the distribution was followed by positron emission tomography for 120 min. The cells were administered either intravenously into the internal jugular vein (n=5) or intraarterially into the ascending aorta (n=1). Two of the pigs given intravenous administration were pretreated with low-molecular-weight dextran sulphate. Results: The cellular kinetics and distribution were readily quantifiable for up to 120 min. High (78.6% of the administered cells) heterogeneous pulmonary uptake was found after completed intravenous transfusion. The pulmonary uptake was decreased either by preineubating and coadministrating the T-Iymphoblasts with low-molecular-weight dextran sulphate or by administrating them intraarterially. Conclusions: The present work shows the feasibility of quantitatively monitoring and evaluating cell trafficking and distribution following administration of [(18)F]FDG-labeled T-Iymphoblasts. The protocol can potentially be transferred to the clinical setting with few modifications.
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34.
  • Eriksson, Olof, et al. (author)
  • In vivo and in vitro characterization of [18F]-FE-(+)-DTBZ as a tracer for beta-cell mass
  • 2010
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 37:3, s. 357-363
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION: The positron emission tomography (PET) tracer 9-[(18)F]fluoroethyl-(+)-dihydrotetrabenazine ([(18)F]-FE-(+)-DTBZ) is a potential candidate for quantifying beta-cell mass in vivo. The purpose was to investigate in vitro and in vivo utility of this tracer for the assessment of beta-cell mass. METHODS: Three pigs were intravenously administered [(18)F]-FE-(+)-DTBZ and examined by PET/computed tomography. Binding parameters were estimated by kinetic modeling. In vitro k(D) and B(max) were determined by saturation binding studies of endocrine and exocrine human tissue homogenates. In vitro pancreatic uptake was determined by tissue autoradiography with pancreases from patients with types 1 (T1DM) and 2 diabetes mellitus (T2DM) and healthy controls. RESULTS: [(18)F]-FE-(+)-DTBZ had a k(D) of 3.5+/-1.0 nM, a B(max) of 382+/-108 fmol/mg protein and a specificity of 89+/-1.8% in islet homogenates. The total exocrine uptake was lower and 65% was nondisplaceable. No uptake difference was observed in pancreatic tissue slices from patients with T1DM, T2DM or healthy controls. The in vivo porcine pancreatic uptake reached a peak of standardized uptake value (SUV) of 2.8 with a low distribution volume ratio in all animals. Moderate to high tracer uptake was identified in the bile system and in bone. CONCLUSIONS: [(18)F]-FE-(+)-DTBZ binds to vesicular monoamine transporter 2 (VMAT2) with high specificity in pure islet tissue in vitro. However, there is high nondisplaceable binding to exocrine tissue. In addition, in vivo tracer metabolism and dehalogenation result in severe underestimation of porcine pancreatic VMAT2 expression and BCM. The results do not support [(18)F]-FE-(+)-DTBZ as a suitable tracer for in vivo beta-cell imaging.
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35.
  • Eriksson, Olof, et al. (author)
  • News ways of understanding the complex biology of diabetes using PET
  • 2021
  • In: Nuclear Medicine and Biology. - : Elsevier. - 0969-8051 .- 1872-9614. ; 92, s. 65-71
  • Research review (peer-reviewed)abstract
    • The understanding of metabolic disease and diabetes on a molecular level has increased significantly due to the recent advances in molecular biology and biotechnology. However, in vitro studies and animal models do not always translate to the human disease, perhaps illustrated by the failure of many drug candidates in the clinical phase. Non-invasive biomedical imaging techniques such as Positron Emission Tomography (PET) offer tools for direct visualization and quantification of molecular processes in humans. Developments in this area potentially enable longitudinal in vivo studies of receptors and processes involved in diabetes guiding drug development and diagnosis in the near future. This mini-review focuses on describing the overall perspective of how PET can be used to increase our understanding and improve treatment of diabetes. The methodological aspects and future developments and challenges are highlighted.
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36.
  • Eriksson, Olof, et al. (author)
  • Positron emission tomography and target-controlled infusion for precise modulation of brain drug concentration
  • 2008
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 35:3, s. 299-303
  • Journal article (peer-reviewed)abstract
    • Introduction: There are several instances when it is desirable to control brain concentration of pharmaceuticals, e.g., to modulate the concentration of anesthetic agents to different desired levels fitting to different needs during the course of surgery. This has so far only been possible using indirect estimates of drug concentration such as assuming constant relation between tissue and blood including extrapolations from animals. Methods: A system for controlling target tissue concentration (UIPump) was used to regulate whole-brain concentrations of a central benzodiazepine receptor antagonist at therapeutic levels with input from brain kinetics as determined with PET. The system was tested by using pharmacological doses of flumazenil mixed with tracer amounts of [C-11]flumazenil. Flumazenil was used as a model compound for anesthesia. An infusion scheme to produce three different steady-state levels in sequence was designed based on kinetic curves obtained after bolus injection. The subjects (Sprague-Dawley rats, n = 6) were monitored in a microPET scanner during the whole experiment to verify resulting brain kinetic curves. Results: A steady-state brain concentration was rapidly achieved corresponding to a whole-brain concentration of 118 +/- 6 ng/ml. As the infusion rate decreased to lower the exposure by a factor of 2, the brain concentration decreased to 56 +/- 4 ng/ml. A third increased steady-state level of anesthesia corresponding to a whole-brain concentration of 107 +/- 7 ng/ml was rapidly achieved. Conclusion: The experimental setup with computerized pump infusion and PET supervision enables accurate setting of target tissue drug concentration.
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37.
  • Eriksson, Olof, et al. (author)
  • Preclinical evaluation of a 68Ga-labeled biotin analogue for applications in islet transplantation
  • 2012
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 39:3, s. 415-421
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION:Islet transplantation is a promising treatment for type 1 diabetes mellitus, but the fate of the cells after intraportal infusion is unclear. It is therefore imperative to develop novel techniques for noninvasive imaging and quantification of events following islet transplantation.METHODS:Small islet-like microbeads, avidin-covered agarose resins (AARs), were used as a model system for islet transplantation. Capability for specific [(68)Ga]Ga-DOTA-(PEG)(2)-biotin uptake and retention for either AARs or human islets conjugated with avidin by means of a heparin scaffold was studied in vitro. Biodistribution of the novel positron emission tomography (PET) tracer [(68)Ga]Ga-DOTA-(PEG)(2)-biotin was evaluated in mice treated by intraportal transplantation of AARs by μPET/computed tomography and ex vivo organ distribution and compared with control mice.RESULTS:AARs had high capability to bind [(68)Ga]Ga-DOTA-(PEG)(2)-biotin, close to 50% of administrated tracer/μl in vitro (>0.25 MBq/μl). Avidin-tagged human islets could bind on average 2.2% of administered tracer/μl. Specificity (>90%) and retention (>90% after 1 h) were high for both AARs and avidin-tagged islets. Hepatic tracer uptake and retention were increased in mice transplanted with AARs [standardized uptake value (SUV)=2.6] compared to the untreated group (SUV=1.4). In vivo uptake of tracer to AARs was blocked by preadministration of unlabeled biotin.CONCLUSIONS:Avidin-tagged islet-like objects can be tracked in hepatic volume after intraportal transplantation by using [(68)Ga]Ga-DOTA-(PEG)(2)-biotin and PET.
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38.
  • Erlandsson, Maria, 1980-, et al. (author)
  • 18F-Labelled Metomidate Analogues as Adrenocortical Imaging Agents
  • 2009
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 36:4, s. 435-445
  • Journal article (peer-reviewed)abstract
    • Introduction: Two- and one-step syntheses of 18F-labelled analogues of Metomidate, such as 2-[18F]fluoroethyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (1), 2-[18F]fluoroethyl 1-[(1R)-1-(4-chlorophenyl)ethyl]-1H-imidazole-5-carboxylate (2), 2-[18F]fluoroethyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (3), 3-[18F]fluoropropyl 1-[(1R)-1-(4-bromophenyl)ethyl]-1H-imidazole-5-carboxylate (4) and 3-[18F]fluoropropyl 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylate (5) are presented.Methods: Analogues 1-5 were prepared by a two-step reaction sequence that started with the synthesis of either 2-[18F]fluoroethyl 4-methylbenzenesulfonate or 3-[18F]fluoropropyl 4-methylbenzenesulfonate. These were used as 18F-alkylating agents in the second step, in which they reacted with the ammonium salt of a 1-[(1R)-1-phenylethyl]-1H-imidazole-5-carboxylic acid. One-step-labelling syntheses of 1, 2 and 5 were also explored. Analogues 1-4 were biological validated by frozen-section autoradiography and organ distribution. Metabolite analysis was performed for 2 and 3.Results: The radiochemical yield of the two-step synthesis was in the range of 10-29%, and thatof the one-step synthesis was 25-37%. Using microwave irradiation in the one-step synthesis of 1 and 2 increased the radiochemical yield to 46 ± 3 and 79 ± 30%, respectively.Conclusion: Both the frozen-section autoradiography and organ distribution results indicated that analogue 2 has a potential as an adrenocortical imaging agent, having the highest degree of specific adrenal binding and best ratio of adrenal to organ uptake among the compounds studied.
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39.
  • Estrada, Sergio, et al. (author)
  • [C-11]UCB-A, a novel PET tracer for synaptic vesicle protein 2 A
  • 2016
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 43:6, s. 325-332
  • Journal article (peer-reviewed)abstract
    • Introduction: Development of a selective and specific high affinity PET tracer, [C-11]UCB-A, for the in vivo study of SV2A expression in humans. Radiochemistry and preclinical studies in rats and pigs including development of a tracer kinetic model to determine V-T. A method for the measurement of percent intact tracer in plasma was developed and the radiation dosimetry was determined in rats. Results: 3-5 GBq of [C-11]UCB-A could be produced with radiochemical purity exceeding 98% with a specific radioactivity of around 65 GBq/mu mol. In vitro binding showed high selective binding towards SV2A. [C-11]UCB-A displayed a dose-dependent and reversible binding to SV2A as measured with PET in rats and pigs and the V-T could be determined by Logan analysis. The dosimetry was favorable and low enough to allow multiple administrations of [C-11]UCB-A to healthy volunteers, and the metabolite analysis showed no sign of labeled metabolites in brain. Conclusions: We have developed the novel PET tracer, [C-11]UCB-A, that can be used to measure SV2A expression in vivo. The dosimetry allows up to 5 administrations of 400 MBq of [C-11]UCB-A in humans. Apart from measuring drug occupancy, as we have shown, the tracer can potentially be used to compare SV2A expression between individuals because of the rather narrow range of baseline V-T values. This will have to be further validated in human studies.
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40.
  • Estrada, Sergio, et al. (author)
  • Preclinical evaluation of [C-11]GW457427 as a tracer for neutrophil elastase
  • 2022
  • In: Nuclear Medicine and Biology. - : Elsevier. - 0969-8051 .- 1872-9614. ; 106-107, s. 62-71
  • Journal article (peer-reviewed)abstract
    • Introduction: Neutrophils are part of the innate immune system and function as a first line of defense against invading microorganisms. Overactivity of the immune system may result in a devastating immuno-inflammation with extensive damage to tissue leading to organ damage and/or failure. The literature suggests several human diseases in which neutrophil elastase (NE) is postulated to be important in the pathophysiology including inflammatory bowel disease (IBD), chronic obstructive pulmonary disorder (COPD), abdominal aortic aneurysms (AAA), breast and lung cancer, and recently also in Sars-cov-2 virus infection (Covid-19). In particular, the lungs are affected by the destructive power of the protease neutrophil elastase (NE). In this paper, we report the pre-clinical development of a selective and specific positron emission tomography (PET) tracer, [C-11] GW457427, as an in vivo biomarker for the study of NE, now available for human studies.Methods: [C-11]GW457427 was produced by methylation of GW447631 using [C-11]methyl triflate and GMP validated production and quality control methods were developed. Chemical purity was high with no traces of the precursor GW611437 or other uv-absorbing compounds. A method for the determination of intact [C-11] GW457427 in plasma was developed and the binding characteristics were evaluated in vitro and in vivo. An animal model for lung inflammation was used to investigate the specificity and sensitivity of the [C-11]GW457427 tracer for neutrophil elastase (NE) in pulmonary inflammation, verified by blockade using two structurally different elastase inhibitors.Results: [C-11]GW457427 was obtained in approximately 45% radiochemical yield and with a radiochemical purity higher than 98%. Molar activity was in the range 130-360 GBq/mu mol. Binding to NE was shown to be highly specific both in vitro and in vivo and a significantly higher uptake of tracer was found in a lipopolysaccharide mouse model of pulmonary inflammation compared with control animals. The uptake in lung tissue measured as standardized uptake value (SUV) strongly correlated with tissue NE content as measured by ELISA. In vitro studies also showed specific tracer binding in aortic tissue of patients with abdominal aorta aneurysm (AAA). The rate of metabolism in rats was appropriate considering the critical balance between available tracer for binding and requirement for blood clearance with about 40% and 20% intact [C-11]GW457427 in plasma at 5 and 40 min, respectively. Radioactivity was cleared from blood and organs in control animals with mainly hepatobiliary excretion with distribution in the intestines and the urinary bladder; but without retention of the tracer in healthy organs of interests such as the lung, liver, kidneys or in the cardiovascular system. A dosimetry study in rat indicated that the whole-body effective dose was 2.2 mu Sv/MBq with bone marrow as the limiting organ. It is estimated that up to five PET-CT investigations could be performed in humans without exceeding a total dose of 10 mSv.Conclusion: [C-11]GW457427 is a promising in vivo PET-biomarker for NE with high specific binding demonstrated both in vitro and in vivo. A GMP validated production method including quality control has been developed and a microdosing toxicity study performed with no adverse signs. [C-11]GW457427 is currently being evaluated in a First-In-Man PET study.
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41.
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42.
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43.
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44.
  • Gustafsson, Anna, et al. (author)
  • Comparison of therapeutic efficacy and biodistribution of (213)Bi- and (211)At-labeled monoclonal antibody MX35 in an ovarian cancer model.
  • 2012
  • In: Nuclear medicine and biology. - : Elsevier BV. - 1872-9614 .- 0969-8051. ; 39:1, s. 15-22
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION: The purpose of this study was to compare the therapeutic efficacy and biodistribution of the monoclonal antibody MX35 labeled with either (213)Bi or (211)At, both α-emitters, in an ovarian cancer model. METHODS: One hundred female nude BALB/c (nu/nu) mice were inoculated intraperitoneally with human ovarian cancer cells (OVCAR-3). Two weeks later, 40 of these mice were injected intraperitoneally with ∼2.7 MBq of (213)Bi-MX35 (n=20) or ∼0.44 MBq of (211)At-MX35 (n=20). Four weeks after inoculation, 40 new OVCAR-3-inoculated mice were injected with the same activities of (213)Bi-MX35 (n=20) or (211)At-MX35 (n=20). Presence of tumors and ascites was investigated 8 weeks after therapy. Biodistributions of intraperitoneally injected (213)Bi-MX35 and (211)At-MX35 were studied in tumor-free nude BALB/c (nu/nu) mice (n=16). RESULTS: The animals injected with (213)Bi-MX35 or (211)At-MX35 2 weeks after cell inoculation had tumor-free fractions (TFFs) of 0.60 and 0.90, respectively. The untreated reference group had a TFF of 0.20. The groups treated with (213)Bi-MX35 or (211)At-MX35 4 weeks after inoculation both had TFFs of 0.25, and the reference animals all exhibited evidence of disease. The biodistributions of (213)Bi-MX35 and (211)At-MX35 were very similar to each other and displayed no alarming activity levels in the investigated organs. CONCLUSIONS: Micrometastatic growth of an ovarian cancer cell line was reduced in nude mice after treatment with (213)Bi-MX35or (211)At-MX35. Treatment with (211)At-MX35 provided a non-significantly better result for the chosen activity levels. The radiolabeled MX35 did not accumulate to a high extent in the investigated organs. No considerable signs of toxicity were observed.
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45.
  • Haller, Stephanie, et al. (author)
  • Folate receptor-targeted radionuclide therapy: preclinical investigation of anti-tumor effects and potential radionephropathy.
  • 2015
  • In: Nuclear medicine and biology. - : Elsevier BV. - 1872-9614 .- 0969-8051. ; 42:10, s. 770-9
  • Journal article (peer-reviewed)abstract
    • Application of therapeutic folate radioconjugates is a promising option for the treatment of folate receptor (FR)-positive tumors, although high uptake of radiofolates in the kidneys remains a critical issue. Recently, it was shown that enhancing the blood circulation of radiofolates results in increased tumor uptake and reduced retention of radioactivity in the kidneys. In this study, we investigated and compared the anti-tumor effects and potential long-term damage to the kidneys after application of an albumin-binding ((177)Lu-cm09), and a conventional ((177)Lu-EC0800) folate radioconjugate.
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46.
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47.
  • Honarvar, Hadis, et al. (author)
  • Evaluation of backbone-cyclized HER2-binding 2-helix Affibody molecule for In Vivo molecular imaging
  • 2013
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 40:3, s. 378-386
  • Journal article (peer-reviewed)abstract
    • Introduction: Affibody molecules, small scaffold proteins, have demonstrated an appreciable potential as imaging probes. Affibody molecules are composed of three alpha-helices. Helices 1 and 2 are involved in molecular recognition, while helix 3 provides stability. The size of Affibody molecules can be reduced by omitting the third alpha-helix and cross-linking the two remaining, providing a smaller molecule with better extravasation and quicker clearance of unbound tracer. The goal of this study was to develop a novel 2-helix Affibody molecule based on backbone cyclization by native chemical ligation (NCL). Methods: The HER2-targeting NCL-cyclized Affibody molecule Z(HER2:342min) has been designed, synthesized and site-specifically conjugated with a DOTA chelator. DOTA-Z(HER2:342min) was labeled with In-111 and (68) Ga. The binding affinity of DOTA-Z(HER2:342min) was evaluated in vitro. The targeting properties of In-111- and (68) Ga-DOTA-Z(HER2:342min) were evaluated in mice bearing SKOV-3 xenografts and compared with the properties of In-111- and (68) Ga-labeled PEP09239, a DOTA-conjugated 2-helix Affibody analogue cyclized by a homocysteine disulfide bridge. Results: The dissociation constant (K-D) for DOTA-Z(HER2:342min) binding to HER2 was 18 nM according to SPR measurements. DOTA-Z(HER2:342min) was labeled with In-111 and (68) Ga. Both conjugates demonstrated bi-phasic binding kinetics to HER2-expressing cells, with K-D1 in low nanbmolar range. Both variants demonstrated specific uptake in HER2-expressing xenografts. Tumor-to-blood ratios at 2 h p.i. were 6.1 +/- 1.3 for In-111-DOTA-Z(HER2:342min) and 4.6 +/- 0.7 for (68) Ga-DOTA-Z(HER2:342min). However, the uptake of DOTA-Z(HER2:342min) in lung, liver and spleen was appreciably higher than the uptake of PEP09239-based counterparts. Conclusions: Native chemical ligation enables production of a backbone-cyclized HER2-binding 2-helix Affibody molecule (Z(HER2:342min)) with low nanomolar target affinity and specific tumor uptake.
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48.
  • Honarvar, Hadis, et al. (author)
  • Evaluation of the first Sc-44-labeled Affibody molecule for imaging of HER2-expressing tumors
  • 2017
  • In: Nuclear Medicine and Biology. - : Elsevier. - 0969-8051 .- 1872-9614. ; 45, s. 15-21
  • Journal article (peer-reviewed)abstract
    • Introduction: Affibody molecules are small (58 amino acids) high-affinity proteins based on a tri-helix nonimmunoglobulin scaffold. A clinical study has demonstrated that PET imaging using Affibody molecules labeled with Ga-68 (T-1/2 = 68 min) can visualize metastases of breast cancer expressing human epidermal growth factor receptor type 2 (HER2) and provide discrimination between tumors with high and low expression level. This may help to identify breast cancer patients benefiting from HER2-targeting therapies. The best discrimination was at 4 h post injection. Due to longer half-life, a positron-emitting radionuclide Sc-44 (T-1/2 = 4.04 h) might be a preferable label for Affibody molecules for imaging at several hours after injection. Methods: A synthetic second-generation anti-HER2 Affibody molecule Z(HER2:2891) was labeled with Sc-44 via a DOTA-chelator conjugated to the N-terminal amino group. Binding specificity, affinity and cellular processing Sc-44-DOTA-Z(HER2:2891) and Ga-68-DOTA-Z(HER2:2891) were compared in vitro using HER2-expressing cells. Biodistribution and imaging properties of Sc-44-DOTA-Z(HER2,2891) and Ga-68-DOTA-Z(HER2:2891) were evaluated in Balb/c nude mice bearing HER2-expression xenografts. Results: The labeling yield of 98 +/- 2% and specific activity of 7.8 GBq/mu mol were obtained. The conjugate demonstrated specific binding to HER2-expressing SKOV3.ip cells in vitro and to SKOV3.ip xenografts in nude mice. The distribution of radioactivity at 3 h post injection was similar for Sc-44-DOTA-Z(HER2:2891) and Ga-68-DOTA-Z(HER2:2891), but the blood clearance of the Sc-44-labeled variant was slower and the tumor-to-blood ratio was reduced (15 +/- 2 for (SC)-S-44-DOTA-Z(HER2:2891) vs 46 +/- 9 for Ga-68-DOTA-Z(HER2.2891)). At 6 h after injection of Sc-44-DOTA-Z(HER2,2891) the tumor uptake was 8 +/- 2% IA/g and the tumor-to-blood ratio was 51 +/- 8. Imaging using small-animal PET/CT demonstrated that (SC)-S-44-DOTA-ZHER2,2891 provides specific and high-contrast imaging of HER2-expressing xenografts. Conclusion: The Sc-44- DOTA-Z(HER2:2891) Affibody molecule is a promising probe for imaging of HER2-expression in malignant tumors.
  •  
49.
  • Ickenstein, Ludger M., et al. (author)
  • A novel I-125-labeled daunorubicin derivative for radionuclide-based cancer therapy
  • 2006
  • In: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 33:6, s. 773-783
  • Journal article (peer-reviewed)abstract
    • INTRODUCTION: Auger electron emitters, such as (125)I, are getting increasingly wider recognition as alternatives to current anticancer treatments. The effectiveness of Auger electrons is strongly dependent on their proximity to DNA and is therefore considered as harmless outside the nucleus. METHODS: (125)I or (127)I was conjugated with Comp1, Comp2 or Comp3 - three derivatives of the chemotherapeutic drug daunorubicin. Their capacity factors, DNA-binding constants and exclusion parameters, and the degree of DNA fragmentation after incubating isolated DNA with our (127)I- or (125)I-conjugated daunorubicin derivatives were determined. Human breast adenocarcinoma (SK-BR-3) cells were incubated with the derivatives; fluorescent microscopy and autoradiography images were generated; and cell growth was monitored. RESULTS AND DISCUSSION: The capacity factor of (127)I-Comp1 was similar to those of daunorubicin and doxorubicin, whereas lower capacity factors of (127)I-Comp2 and (127)I-Comp3 suggested reduced interactions with lipid membranes. DNA exclusion parameters and binding constants of (127)I-Comp1 and (127)I-Comp2, but not of (127)I-Comp3, were similar to those of doxorubicin. Fluorescent microscopy and autoradiography images of SK-BR-3 cells revealed that (127)I-Comp1 and (125)I-Comp1 accumulated in tumor cell nuclei, whereas (127)I-Comp2 and (127)I-Comp3 were present predominantly in other cell compartments. The binding of (125)I-Comp1 to isolated chromosomal DNA led to major fragmentation. Incubation of SK-BR-3 cells with (125)I-Comp1 inhibited cell growth, whereas doxorubicin or (127)I-Comp1 administered at the same concentration had no effect on cell growth. Our results thus suggest that (125)I-Comp1 has the potential to become a new tool for anticancer therapy.
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50.
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