| 1. |
- Altai, Mohamed, et al.
(författare)
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Evaluation of affibody molecule-based PNA-mediated radionuclide pretargeting : Development of an optimized conjugation protocol and 177Lu labeling
- 2017
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Ingår i: Nuclear Medicine and Biology. - : Elsevier. - 0969-8051 .- 1872-9614. ; 54, s. 1-9
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Coenen, Heinz H., et al.
(författare)
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Consensus nomenclature rules for radiopharmaceutical chemistry - Setting the record straight
- 2017
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Ingår i: Nuclear Medicine and Biology. - : ELSEVIER SCIENCE INC. - 0969-8051 .- 1872-9614. ; 55, s. V-XI
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Tidskriftsartikel (refereegranskat)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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| 3. |
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| 4. |
- Eriksson, Jonas, et al.
(författare)
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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
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 71, s. 1-10
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Estrada, Sergio, et al.
(författare)
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[C-11]UCB-A, a novel PET tracer for synaptic vesicle protein 2 A
- 2016
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 43:6, s. 325-332
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Tidskriftsartikel (refereegranskat)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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| 6. |
- Haller, Stephanie, et al.
(författare)
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Folate receptor-targeted radionuclide therapy: preclinical investigation of anti-tumor effects and potential radionephropathy.
- 2015
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Ingår i: Nuclear medicine and biology. - : Elsevier BV. - 1872-9614 .- 0969-8051. ; 42:10, s. 770-9
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Tidskriftsartikel (refereegranskat)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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| 7. |
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| 8. |
- Honarvar, Hadis, et al.
(författare)
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Evaluation of the first Sc-44-labeled Affibody molecule for imaging of HER2-expressing tumors
- 2017
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Ingår i: Nuclear Medicine and Biology. - : Elsevier. - 0969-8051 .- 1872-9614. ; 45, s. 15-21
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Tidskriftsartikel (refereegranskat)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.
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| 9. |
- Jahan, M., et al.
(författare)
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Synthesis and biological evaluation of [C-11]AZ12504948; a novel tracer for imaging of glucokinase in pancreas and liver
- 2015
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 42:4, s. 387-394
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Glucokinase (GK) is potentially a target for imaging of islets of Langerhans. Here we report the radiosynthesis and preclinical evaluation of the GK activator, [C-11]AZ12504948, for in vivo imaging of GK. Methods: [C-11]AZ12504948 was synthesized by O-methylation of the precursor, AZ125555620, using carbon-11 methyl iodide ([C-11]CH3I).Preclinical evaluation was performed by autoradiography (ARC) of human tissues and PET/CT studies in pig and non-human primate. Result: [C-11]AZ12504948 was produced in reproducible good radiochemical yield in 28-30 min. Radiochemical purity of the formulated product was >98% for up to 2 h with specific radioactivities 855 +/- 209 GBq/mu mol (n = 8). The preclinical evaluation showed some specificity for GK in liver, but not in pancreas. Conclusion:[C-11]AZ12504948 images GK in liver, but the low specificity impedes the visualization of GK in pancreas. Improved target specificity is required for further progress using PET probes based on this class of GK activators.
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| 10. |
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| 11. |
- Karlsson, Filip, et al.
(författare)
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Systematic screening of imaging biomarkers for the Islets of Langerhans, among clinically available positron emission tomography tracers
- 2015
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 42:10, s. 762-769
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Functional imaging could be utilized for visualizing pancreatic islets of Langerhans. Therefore, we present a stepwise algorithm for screening of clinically available positron emission tomography (PET) tracers for their use in imaging of the neuroendocrine pancreas in the context of diabetes. Methods: A stepwise procedure was developed for screening potential islet imaging agents. Suitable PET-tracer candidates were identified by their molecular mechanism of targeting. Clinical abdominal examinations were retrospectively analyzed for pancreatic uptake and retention. The target protein localization in the pancreas was assessed in silico by -omics approaches and the in vitro by binding assays to human pancreatic tissue. Results: Six putative candidates were identified and screened by using the stepwise procedure. Among the tested PET tracers, only [C-11]5-Hydroxy-tryptophan passed all steps. The remaining identified candidates were falsified as candidates and discarded following in silico and in vitro screening. Conclusions: Of the six clinically available PET tracers identified, [C-11]5-HTP was found to be a promising candidate for beta cell imaging, based on intensity of in vivo pancreatic uptake in humans, and islet specificity as assessed on human pancreatic cell preparations. The flow scheme described herein constitutes a methodology for evaluating putative islet imaging biomarkers among clinically available PET tracers.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Rahman, Obaidur, et al.
(författare)
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Synthesis of ([C-11]carbonyl)raclopride and a comparison with ([C-11]methyl)raclopride in a monkey PET study
- 2015
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 42:11, s. 893-898
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The selective dopamine D-2 receptor antagonist raclopride is usually labeled with carbon-11 using [C-11]methyl iodide or [C-11]methyl triflate for use in the quantification of dopamine D-2 receptors in human brain. The aim of this work was to label raclopride at the carbonyl position using [C-11]carbon monoxide chemistry and to compare ([C-11]carbonyl)raclopride with ([C-11]methyl)raclopride in non-human primate (NHP) using PET with regard to quantitative outcome measurement, metabolism of the labeled tracers and protein binding. Methods: Palladium-mediated carbonylation using [C-11]carbon monoxide, 4,6-dichloro-2-iodo-3-methoxyphenol and (S)-(-)-2-aminomethyl-1-ethylpyrrolidine was applied in the synthesis of ([C-11]carbonyl)raclopride. The reaction was performed at atmospheric pressure using xantphos as supporting phosphine ligand and palladium (pi-cinnamyl) chloride dimer as the palladium source. ([C-11]Methyl)raclopride was prepared by a previously published method. In the PET study, two female cynomolgus monkeys were used under gas anesthesia of sevoflurane. A dynamic PET measurement was performed for 63 min with an HRRT PET camera after intravenous injection of ([C-11]carbonyl)raclopride and ([C-11]methyl)raclopride, respectively, during the same day. The order of injection of the two PET radioligands was changed between the two monkeys. The venous blood sample for measurement of protein binding was taken 3 min prior to the PET scan. Binding potential (BPND) of the putamen and caudate was calculated with SRTM using the cerebellum as a reference region. Results: The target compound ([C-11]carbonyl)raclopride was obtained with 50 +/- 5% decay corrected radiochemical yield and 95% radiochemical purity. The trapping efficiency (TE) of [C-11]carbon monoxide was 65 +/- 5% and the specific radioactivity of the final product was 34 +/- 1 GBq/mu mol after a 50 min of synthesis time. The radiochemical yield of ([C-11]methyl)raclopride was in the same range as published previously i.e. 50-60% and specific radioactivity of those two batches which were used in the present PET study were 192 GBq/mu mol and 638 GBq/mu mol respectively after a synthesis time of 32 min. In monkey PET studies, the percentage difference of BPND in putamen was <3% and that in caudate was <9% for the two radioligands. The plasma protein binding was 86.2 +/- 0.3% and 85.7 +/- 0.6% for ([C-11]carbonyl)raclopride and ([C-11]methyl)raclopride, respectively. The radiometabolite pattern was similar for both radioligands. Conclusion: Raclopride was C-11-labeled at the carbonyl position using a palladium-mediated [C-11]carbonylation reaction. A comparison between ([C-11]carbonyl)raclopride and ([C-11]merhyl)raclopride with regard to quantitative PET outcome measurements, metabolism of radioligands and protein binding in monkey was performed. The monkey PET study with ([C-11]carbonyl)raclopride showed similar results as for ([C-11]methyl)raclopride. The PET studies were performed on 2 subjects.
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| 16. |
- Rudqvist, Nils, et al.
(författare)
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Dose-specific transcriptional responses in thyroid tissue in mice after (131)I administration.
- 2015
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Ingår i: Nuclear medicine and biology. - : Elsevier BV. - 1872-9614 .- 0969-8051. ; 42:3, s. 263-8
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Tidskriftsartikel (refereegranskat)abstract
- In the present investigation, microarray analysis was used to monitor transcriptional activity in thyroids in mice 24 h after (131)I exposure. The aims of this study were to 1) assess the transcriptional patterns associated with (131)I exposure in normal mouse thyroid tissue and 2) propose biomarkers for (131)I exposure of the thyroid.
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| 17. |
- Rydén, Anneli, et al.
(författare)
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Cardiovascular side-effects and insulin secretion after intravenous administration of radiolabeled Exendin-4 in pigs
- 2016
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 43:7, s. 397-402
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Radiolabeled Exendin-4, a synthetic glucagon-like peptide-1 (GLP-1) analog, is used as a tracer for diagnostic purposes of beta-cells and in experimental animal research. Exendin-4 can be radiolabeled with Ga-68, I-111 n or (99)mTc and used for positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging to diagnose insulinomas, visualization of pancreatic beta-cell mass and transplanted Islets of Langerhans. In humans, Exendin-4 is widely used as a therapeutic agent for treatment of type 2 diabetes (T2D). The compound, which is administered subcutaneously (SC) may cause nausea, vomiting and a minor increase in the heart rate (HR). However, possible side-effects on cardiovascular functions after intravenous (IV) administration have not been reported. This study describes the Exendin-4 dose at which cardiovascular side-effects occur in pigs and cynomolgus monkeys. The IV effect of the tracer on insulin secretion is also investigated in pigs. Methods: Seven clinically healthy littermate pigs (40 days old) were used; three of them were made diabetic by streptozotocin (STZ). All pigs underwent PET imaging under general anesthesia to examine the glucagon-like peptide-1 receptor (GLP-1R) in beta-cells with radiolabeled Exendin-4. A baseline tracer dose IV [Ga-68]Exendin-4 (0.025 +/- 0.010 mu g/kg) followed by a competition dose IV [Ga-68]Exendin-4 (3.98 +/- 133 mu g/kg) 60 min later were administered. Blood samples were taken and analyzed for insulin secretion by using ELISA. Cardiovascular and respiratory variables were monitored throughout the experiment. Results: Immediately after administration of the high dose [Ga-68]Exendin-4 the HR rose from 122 14 to 227 +/- 40 bpm (p < 0.01) and from 100 +/- 5 to 181 +/- 13 bpm (p < 0.01) in healthy non -diabetic and diabetes-induced pigs, respectively. The tachycardia was observed for >2 h and one healthy non-diabetic pig suffered cardiac arrest 3 h after the IV [Ga-68]Exendin-4. Arrhythmia was detected by listening to the heart with a stethoscope up to 4 days after the [Ga-68]Exendin-4 injection. In all animals, no effect on the cardiovascular system was registered after the low dose of IV [Ga-68]Exendin-4. Insulin secretion increased (p < 0.05) when IV [Ga-68]Exendin-4 was given in dosages >= 0.14 mu g/kg. Conclusions: Intravenous administration of mu g/kg [Ga-68]Exendin-4 resulted in severe tachycardia and arrhythmias in healthy non -diabetic and diabetes-induced pigs, and the insulin secretion was stimulated in healthy non diabetic animals when >= 0.14 mu g/kg [Ga-68]Exendin-4 was given.
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| 18. |
- Spiegelberg, Diana, et al.
(författare)
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A real-time in vitro assay as a potential predictor of in vivo tumor imaging properties
- 2016
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 43:1, s. 12-18
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Selective tumor targeting strategies based on cell surface molecules enable new personalized diagnosis and treatments, potentially lowering adverse effects and increasing efficacy. Radio-immunotargeting generally relies on a molecule binding to a cancer-specific target. It is therefore important to understand the properties of molecular interactions in their working environment and how to translate these properties measured in vitro into the in vivo molecular imaging situation. Methods: Time resolved interaction analysis in vitro was compared with a corresponding in vivo xenograft mouse model. The antibody fragment AbD15179 was labeled with I-125 or In-111, and analyzed on cell lines with differing CD44v6 expression in vitro, and in a dual tumor xenograft model derived from the same cell lines. In vitro LigandTracer measurements were analyzed with TraceDrawer and Interaction Map. Conjugate sensitivity, kinetics, and signal-to-background ratios were assessed for both tumor cells in vitro and xenograft tumors in vivo. Results: In vitro results revealed a general biphasic appearance of a high- and a low-affinity interaction event. The In-111-labeled fragment displayed the largest proportion of the high-affinity interaction with increased sensitivity and retention compared to I-125-Fab. In vivo results were in agreement with in vitro data, with increased retention, higher sensitivity and better contrast for the In-111-labeled fragment compared to I-125. Conclusions: Time resolved binding characteristics measured in vitro largely matched the in vivo performance for the conjugates, which is promising for future studies. In vitro time-resolved LigandTracer assays are efficient, rapid, and in this study shown to be able to predict in vivo outcomes. Advances in Knowledge and Implications for Patient Care: Further studies are needed to confirm these findings, but the method is promising considering the ethical need to reduce the use of laboratory animals, as well as reducing costs for the development of tumor targeting compounds in the future.
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| 19. |
- Stepanov, Vladimir, et al.
(författare)
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Development of [C-11]/[H-3-1]THK-5351-A potential novel carbon-11 tau imaging PET radioligand
- 2017
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 46, s. 50-53
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Due to the rise in the number of patients with dementia the imperative for finding new diagnostic and treatment options becomes ever more pressing. While significant progress has been made in PET imaging of A beta aggregates both in vitro and in vivo, options for imaging tau protein aggregates selectively are still limited. Based on the work previously published by researchers from the Tohoku University, Japan, that resulted in the development of [F-18]THK-5351, we have undertaken an effort to develop a carbon-11 version of the identical structure - [C-11]THK-5351. In parallel, THK-5351 was also labeled with tritium ([H-3]THK-5351) for use in in vitro autoradiography (ARG). Methods: The carbon -11 labeling was performed starting with di-protected enantiomeric pure precursor-tertbutyl 5-(6-( (2S)-3-fluoro-2-(tetrahydro-2H-Pyran-2-yloxy)proPoxy)quinolin-2-yl)pyridin-2-yl carbamate, which was reacted with [C-11]MeI, using DMF as the solvent and NaH as base, followed by deprotection with trifluoroacetic acid/water mixture, resulting in enantiomerically pure carbon-11 radioligand,[C-11]THK-5351 (S)-1-fluoro-3-(2-(6-([C-11]methylamino)pyridin-3-yl)quinolin-6-yloxy)propan-2-ol. Tritium labeling and purification of [H-3]THK-5351 were undertaken using similar approach, resulting in [H-3]THK-5351 with RCP >99.8% and specific radioactivity of 13 GB q/mu mol. Results: [C-11]THK-5351 was produced in good yield (1900 +/- 355 MBq), specific radioactivity (SRA) (361 +/- 119 GBq/mu rnol at EOS + 20 min) and radiochemical purity (RCP) (>99.8%), with enantiomeric purity of 98.7%. [H-3]TM-5351 was evaluated for ARG of tau binding in post-mortem human brain tissue using cortical sections from one AD patient and one control subject. [H-3]THK-5351 binding density was higher in the AD patient compared to the control subject, the binding was displaced by unlabeled THK-5351 confirming specific [H-3] THK-5351 binding. (C) 2016 Elsevier Inc. All rights reserved.
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| 20. |
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| 21. |
- Varasteh, Zohreh, et al.
(författare)
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The effect of macrocyclic chelators on the targeting properties of the 68Ga-labeled gastrin releasing peptide receptor antagonist PEG2-RM26
- 2015
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 42:5, s. 446-454
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionOverexpression of gastrin-releasing peptide receptors (GRPR) has been reported in several cancers. Bombesin (BN) analogs are short peptides with a high affinity for GRPR. Different BN analogs were evaluated for radionuclide imaging and therapy of GRPR-expressing tumors. We have previously investigated an antagonistic analog of BN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2, RM26) conjugated to NOTA via a PEG2 spacer (NOTA-PEG2-RM26) labeled with 68Ga, 111In and Al18F. 68Ga-labeled NOTA-PEG2-RM26 showed high tumor-to-organ ratios.MethodsThe influence of different macrocyclic chelators (NOTA, NODAGA, DOTA and DOTAGA) on the targeting properties of 68Ga-labeled PEG2-RM26 was studied in vitro and in vivo.ResultsAll conjugates were labeled with generator-produced 68Ga with high yields and demonstrated high stability and specific binding to GRPR. The IC50 values of natGa-X-PEG2-RM26 (X = NOTA, DOTA, NODAGA, DOTAGA) were 2.3 ± 0.2, 3.0 ± 0.3, 2.9 ± 0.3 and 10.0 ± 0.6 nM, respectively. The internalization of the conjugates by PC-3 cells was low. However, the DOTA-conjugated analog demonstrated a higher internalization rate compared to other analogs. GRPR-specific uptake was found in receptor-positive normal tissues and PC-3 xenografts for all conjugates. The biodistribution of the conjugates was influenced by the choice of the chelator moiety. Although all radiotracers cleared rapidly from the blood, [68Ga]Ga-NOTA-PEG2-RM26 showed significantly lower uptake in lung, muscle and bone compared to the other analogs. The uptake in tumors (5.40 ± 1.04 %ID/g at 2 h p.i.) and the tumor-to-organ ratios (25 ± 3, 157 ± 23 and 39 ± 4 for blood, muscle and bone, respectively) were significantly higher for the NOTA-conjugate than the other analogs.ConclusionsChelators had a clear influence on the biodistribution and targeting properties of 68Ga-labeled antagonistic BN analogs. Positively charged [68Ga]Ga-NOTA-PEG2-RM26 provided a low kidney radioactivity uptake, high affinity, high tumor uptake and high image contrast.
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| 22. |
- Vilhelmsson Timmermand, Oskar, et al.
(författare)
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Radiolabeled antibodies in prostate cancer: A case study showing the effect of host immunity on antibody bio-distribution.
- 2015
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 1872-9614 .- 0969-8051. ; 42:4, s. 375-380
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Tidskriftsartikel (refereegranskat)abstract
- Human tumors xenografted in immunodeficient mice are crucial models in nuclear medicine to evaluate the effectiveness of candidate diagnostic and therapeutic compounds. However, little attention has been focused on the biological profile of the host model and its potential effects on the bio-distribution and tumor targeting of the tracer compound under study. We specifically investigated the dissimilarity in bio-distribution of (111)In-DTPA-5A10, which targets free prostate specific antigen (fPSA), in two animal models.
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| 23. |
- Spetz, Johan, et al.
(författare)
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Time-dependent transcriptional response of GOT1 human small intestine neuroendocrine tumor after 177Lu-octreotate therapy
- 2018
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051. ; 60, s. 11-18
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Patients with neuroendocrine tumors expressing somatostatin receptors are often treated with 177Lu-octreotate. Despite being highly effective in animal models, 177Lu-octreotate-based therapies in the clinical setting can be optimized further. The aims of the study were to identify and elucidate possible optimization venues for 177Lu-octreotate tumor therapy by characterizing transcriptional responses in the GOT1 small intestine neuroendocrine tumor model in nude mice. Methods: GOT1-bearing female BALB/c nude mice were intravenously injected with 15 MBq 177Lu-octreotate (non-curative amount) or mock-treated with saline solution. Animals were killed 1, 3, 7 or 41 d after injection. Total RNA was extracted from the tumor samples and profiled using Illumina microarray expression analysis. Differentially expressed genes were identified (treated vs. control) and pathway analysis was performed. Results: Distribution of differentially expressed transcripts indicated a time-dependent treatment response in GOT1 tumors after 177Lu-octreotate administration. Regulation of CDKN1A, BCAT1 and PAM at 1 d after injection was compatible with growth arrest as the initial response to treatment. Upregulation of APOE and BAX at 3 d, and ADORA2A, BNIP3, BNIP3L and HSPB1 at 41 d after injection suggests first activation and then inhibition of the intrinsic apoptotic pathway during tumor regression and regrowth, respectively. Conclusion: Transcriptional analysis showed radiation-induced apoptosis as an early response after 177Lu-octreotate administration, followed by pro-survival transcriptional changes in the tumor during the regrowth phase. Time-dependent changes in cell cycle and apoptosis-related processes suggest different time points after radionuclide therapy when tumor cells may be more susceptible to additional treatment, highlighting the importance of timing when administering multiple therapeutic agents. © 2017
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