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2. Microscale radiosynthesis, preclinical imaging and dosimetry study of [18F]AMBF3-TATE: A potential PET tracer for clinical imaging of somatostatin receptors

Author

Lisova, Ksenia, Sergeev, Maxim, Evans-Axelsson, Susan, Stuparu, Andreea D, Beykan, Seval, Collins, Jeffrey, Jones, Jason, Lassmann, Michael, Herrmann, Ken, Perrin, David, Lee, Jason T, Slavik, Roger, and van Dam, R Michael

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Bioengineering, Cancer, Biotechnology, Biomedical Imaging, Neurosciences, Urologic Diseases, 4.1 Discovery and preclinical testing of markers and technologies, Good Health and Well Being, Animals, Boron Compounds, Cell Line, Tumor, Fluorine Radioisotopes, Lab-On-A-Chip Devices, Mice, Octreotide, Positron Emission Tomography Computed Tomography, Radioactive Tracers, Radiochemistry, Radiometry, Receptors, Somatostatin, Tumor-targeting peptide, Neuroendocrine tumors, SSTR2 imaging, Microfluidic radiochemistry, Trifluoroborate, Clinical translation, Nuclear Medicine & Medical Imaging, Clinical sciences
Abstract

BackgroundPeptides labeled with positron-emitting isotopes are emerging as a versatile class of compounds for the development of highly specific, targeted imaging agents for diagnostic imaging via positron-emission tomography (PET) and for precision medicine via theranostic applications. Despite the success of peptides labeled with gallium-68 (for imaging) or lutetium-177 (for therapy) in the clinical management of patients with neuroendocrine tumors or prostate cancer, there are significant advantages of using fluorine-18 for imaging. Recent developments have greatly simplified such labeling: in particular, labeling of organotrifluoroborates via isotopic exchange can readily be performed in a single-step under aqueous conditions and without the need for HPLC purification. Though an automated synthesis has not yet been explored, microfluidic approaches have emerged for 18F-labeling with high speed, minimal reagents, and high molar activity compared to conventional approaches. As a proof-of-concept, we performed microfluidic labeling of an octreotate analog ([18F]AMBF3-TATE), a promising 18F-labeled analog that could compete with [68Ga]Ga-DOTATATE with the advantage of providing a greater number of patient doses per batch produced.MethodsBoth [18F]AMBF3-TATE and [68Ga]Ga-DOTATATE were labeled, the former by microscale methods adapted from manual labeling, and were imaged in mice bearing human SSTR2-overexpressing, rat SSTR2 wildtype, and SSTR2-negative xenografts. Furthermore, a dosimetry analysis was performed for [18F]AMBF3-TATE.ResultsThe micro-synthesis exhibited highly-repeatable performance with radiochemical conversion of 50 ± 6% (n = 15), overall decay-corrected radiochemical yield of 16 ± 1% (n = 5) in ~40 min, radiochemical purity >99%, and high molar activity. Preclinical imaging with [18F]AMBF3-TATE in SSTR2 tumor models correlated well with [68Ga]Ga-DOTATATE. The favorable biodistribution, with the highest tracer accumulation in the bladder followed distantly by gastrointestinal tissues, resulted in 1.26 × 10-2 mSv/MBq maximal estimated effective dose in human, a value lower than that reported for current clinical 18F- and 68Ga-labeled compounds.ConclusionsThe combination of novel chemical approaches to 18F-labeling and microdroplet radiochemistry have the potential to serve as a platform for greatly simplified development and production of 18F-labeled peptide tracers. Favorable preclinical imaging and dosimetry of [18F]AMBF3-TATE, combined with a convenient synthesis, validate this assertion and suggest strong potential for clinical translation.

Published
2018

3. Synthesis and preclinical evaluation of an Al18F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand

Author

Boschi, Stefano, Lee, Jason T, Beykan, Seval, Slavik, Roger, Wei, Liu, Spick, Claudio, Eberlein, Uta, Buck, Andreas K, Lodi, Filippo, Cicoria, Gianfranco, Czernin, Johannes, Lassmann, Michael, Fanti, Stefano, and Herrmann, Ken

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Biomedical Imaging, Cancer, Bioengineering, Animals, Antigens, Surface, Biomarkers, Tumor, Cell Line, Tumor, Drug Evaluation, Preclinical, Edetic Acid, Fluorine Radioisotopes, Gallium Isotopes, Gallium Radioisotopes, Glutamate Carboxypeptidase II, Isotope Labeling, Male, Metabolic Clearance Rate, Mice, Mice, Inbred C57BL, Oligopeptides, Organ Specificity, Organometallic Compounds, Positron-Emission Tomography, Prostatic Neoplasms, Radiation Dosage, Radiation Exposure, Radiopharmaceuticals, Reproducibility of Results, Sensitivity and Specificity, Tissue Distribution, Whole-Body Counting, PET, PSMA, F-18, Dosimetry, Preclinical, Prostate cancer, 18F, Other Physical Sciences, Nuclear Medicine & Medical Imaging, Clinical sciences
Abstract

PurposeThe aim of this study was to synthesize and preclinically evaluate an 18F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined.MethodsSeveral conditions for the labeling of 18F-PSMA-11 via 18F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed.ResultsQuantitative labeling yields could be achieved with >97 % radiochemical purity. The 18F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p

Published
2016

4. Biodistribution and Radiation Dosimetry for a Probe Targeting Prostate-Specific Membrane Antigen for Imaging and Therapy

Author

Herrmann, Ken, Bluemel, Christina, Weineisen, Martina, Schottelius, Margret, Wester, Hans-Jürgen, Czernin, Johannes, Eberlein, Uta, Beykan, Seval, Lapa, Constantin, Riedmiller, Hubertus, Krebs, Markus, Kropf, Saskia, Schirbel, Andreas, Buck, Andreas K, and Lassmann, Michael

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Urologic Diseases, Biomedical Imaging, Bioengineering, Cancer, Aged, Antigens, Surface, Bone Marrow, Edetic Acid, Gallium Isotopes, Gallium Radioisotopes, Glutamate Carboxypeptidase II, Humans, Kidney, Male, Middle Aged, Oligopeptides, Positron-Emission Tomography, Prostatic Neoplasms, Radiometry, Radiopharmaceuticals, Salivary Glands, Spleen, Tissue Distribution, Whole Body Imaging, PET, PSMA, Ga-68, dosimetry, prostate cancer, 68Ga, Nuclear Medicine & Medical Imaging, Clinical sciences
Abstract

UnlabelledProstate-specific membrane antigen (PSMA) is a promising target for diagnosis and treatment of prostate cancer. EuK-Subkff-(68)Ga-DOTAGA ((68)Ga-PSMA Imaging & Therapy [PSMA I&T]) is a recently introduced PET tracer for imaging PSMA expression in vivo. Whole-body distribution and radiation dosimetry of this new probe were evaluated.MethodsFive patients with a history of prostate cancer were injected intravenously with 91-148 MBq of (68)Ga-PSMA I&T (mean ± SD, 128 ± 23 MBq). After an initial series of rapid whole-body scans, 3 static whole-body scans were acquired at 1, 2, and 4 h after tracer injection. Time-dependent changes of the injected activity per organ were determined. Mean organ-absorbed doses and effective doses were calculated using OLINDA/EXM.ResultsInjection of 150 MBq of (68)Ga-PSMA I&T resulted in an effective dose of 3.0 mSv. The kidneys were the critical organ (33 mGy), followed by the urinary bladder wall and spleen (10 mGy each), salivary glands (9 mGy each), and liver (7 mGy).Conclusion(68)Ga-PSMA I&T exhibits a favorable dosimetry, delivering organ doses that are comparable to (kidneys) or lower than those delivered by (18)F-FDG.

Published
2015

8. Implementierung und Optimierung der Dosimetrie für die Theranostik in Radiopeptidtherapien

Author

Beykan, Seval

Subjects
ddc:610, 610 Medizin und Gesundheit
Abstract

Peptide receptor radionuclide therapy (PRRT) is a molecular targeted radiation therapy involving the systemic administration of radiolabeled somatostatin receptor binding peptides designed to target with high affinity and specificity receptors overexpressed on tumors. Peptides are applied which either target as agonist (with internalization) or antagonist (little to no internalization). Recently, two novel antagonistic agents have been developed for clinical use: OPS202 and OPS201. 68Ga-labelled OPS202 is used for diagnostic purposes with positron emission tomography and 177Lu-labelled OPS201 is used for the therapy in patients with neuroendocrine tumors (NETs). Both agents are presently under clinical evaluation. Despite the very low internalization rate, the use of somatostatin receptor antagonists which target more binding sites on receptors are expected to result in higher specificity, more favorable pharmacokinetics and higher tumor retention and better visualization than the agonists. The main goal of this thesis was analyzing the biodistribution, biokinetics and internal dosimetry of the recently developed somatostatin receptor antagonists (OPS201 and OPS202) for therapeutic and diagnostic purposes in different species (mice, pigs and patients). In addition, an analysis of the influence of image quantification and the integration of time activity curves on kidney dosimetry in a pig model was carried out. Furthermore, extrapolation methods, which are used for predicting organ absorbed doses for humans based on preclinical animal models, were systematically compared for blood, liver, and kidneys of OPS201 injected species. Based on the OPS202 injected patients’ investigations, 68Ga-OPS202 shows promising biodistribution and imaging properties with tumor contrast which is optimal one hour after injection of the radiotracer. OPS202 is well tolerated and delivers absorbed doses to organs that are lower than those by 18F-FDG and similar to other 68Ga-labeled somatostatin receptor ligands. As a result of 68Ga OPS202 injection, the highest absorbed doses were observed in the urinary bladder (0.10 mGy/MBq) and kidneys (0.84 mGy/MBq). The calculated mean effective dose coefficient of 68Ga-OPS202 injected patients was 0.024 mSv/MBq (3.6 mSv for 150 MBq 68Ga-OPS202 injection) which is similar to other 68Ga-labeled compounds. Based on the OPS201 biokinetics and dosimetry investigations, after the injection of 177Lu-OPS201, a fast blood clearance of the compound is observed in the first phase (half-life: 1.83 h) for each species. 10 min after injection, less than 5% of the injected activity per milliliter of blood circulates in pigs and humans. The analysis of the mice, pig and preliminary patient data provides evidence that, patients enrolled in a phase 1 177Lu-OPS201 trial would not be at risk of overexposure. Based on our results, for 177Lu labelled studies, late time points after 72 h have a great impact on absorbed dose calculations. That is why follow-up times especially at late time points (more than 72 h) are required for the time-integrated activity coefficient (TIAC) calculations in order to represent the area under the curve appropriately and to analyze both biokinetics and dosimetry accurately. In addition, to find the most adequate extrapolation methods that minimize the interspecies differences of dosimetry data, several extrapolation methods from animal to human have been tested. For OPS201 time scaling or combination of relative mass and time scaling results in most similar TIAC values, if the organ mass ratios between the species are high. In time scaling, the scan/sampling time is scaled by using the ratio of the whole body masses of the respective species. In relative mass scaling, the TIACs are scaled based on the ratio of the whole body and organ mass of respective species. Other methods tested showed higher deviations. For the study on the influence of image quantification and the choice of the optimal scanning time points, a study in a pig model, which was performed in collaboration with Aalborg University and Octreopharm Sciences GmbH, was reanalyzed. As kidneys are organs-at-risk in PRRT with 177Lu labelled peptides, several quantification methods, based on 2D and 3D quantitative imaging were chosen. For this purpose, a 3D printed pig kidney phantom was prepared and measured with/without background activities representing the activities in the pig SPECT/CT scans. The phantom dosimetry data based on multiple SPECT/CT images and based on multiple planar images in combination with one SPECT/CT scan (MP1S Imaging) were compared to the pig dosimetry. The calculated TIACs of the phantom with background based on multiple SPECT/CT and MP1S imaging were quite similar to the multiple SPECT/CT based pig TIAC. In addition, in order to investigate the effect of late time points on dosimetry and absorbed dose values in 177Lu therapies, the difference, associated with eliminating the late two scan time points, on the TIACs was analyzed. When the TIACs (including all time points) of the pig based on multiple SPECT/CT and MP1S imaging were investigated, the use of MP1S imaging results in considerably lower TIAC values to the kidney (by a factor of 1.4). With eliminating late time points from the created time activity curve, the factor increases up to 2.4 times with a corresponding increase in TIAC uncertainties. As a consequence, further evaluation of 68Ga-OPS202 for PET/CT imaging and 177Lu-OPS201 for the treatments of NET patients is necessary. In particular, a head-to-head comparison of agonists and OPS peptides with respect to biokinetics, biodistribution and dosimetry would be helpful. In addition, the influence of the late scan time points on dosimetry needs further attention in particular for kidney dosimetry, Die Peptidrezeptor-Radionuklidtherapie (PRRT) beinhaltet die systemische Verabreichung von radioaktiv markierten Somatostatinrezeptor-bindende Peptiden. Sie zielt darauf ab, Rezeptoren, die in Tumoren überexprimiert sind, mit hoher Affinität und Spezifität anzusprechen. Es werden Peptide eingesetzt, die entweder als Agonist (mit Internalisierung) oder Antagonist (wenig bis gar keine Internalisierung) wirken. Vor kurzem wurden zwei neue antagonistische Wirkstoffe für den klinischen Einsatz entwickelt: OPS202 und OPS201. 68Ga markiertes OPS202 wird für diagnostische Zwecke mit der Positronen-Emissions-Tomographie und 177Lu markiertes OPS201 für die Therapie von Patienten mit neuroendokrinen Tumoren (NETs) verwendet. Beide Wirkstoffe befinden sich derzeit in der klinischen Erprobung. Trotz der sehr niedrigen Internalisierungsrate wird erwartet, dass der Einsatz von Somatostatinrezeptor-Antagonisten, die mehr Bindungsstellen an Rezeptoren ansprechen, zu einer höheren Spezifität, einer günstigeren Pharmakokinetik und einer höheren Tumorretention und besseren Visualisierung als die Agonisten führt. Das Hauptziel dieser Arbeit war die Analyse der Biodistribution, Biokinetik und der internen Dosimetrie der neu entwickelten Somatostatinrezeptor-Antagonisten (OPS201 und OPS202) für therapeutische und diagnostische Zwecke in verschiedenen Spezies (Mäuse, Schweine und Patienten). Darüber hinaus wurde eine Analyse des Einflusses der Bildquantifizierung und der Integration von Zeitaktivitätskurven auf die Nierendosimetrie in einem Schweinemodell durchgeführt. Zudem wurden Extrapolationsmethoden, die zur Vorhersage der Energiedosen für das Blut, die Leber und die Nieren für den Menschen auf der Grundlage präklinischer Tiermodelle, die mit OPS201 injiziert wurden, systematisch verglichen. Basierend auf den Patientenuntersuchungen mit OPS202 zeigt 68Ga-OPS202 vielversprechende Biodistributions- und Abbildungseigenschaften mit einem Tumorkontrast, der eine Stunde nach Injektion des Radiotracers optimal ist. OPS202 ist gut verträglich; die Energiedosen in den Organen sind niedriger als die von 18F-FDG und ähnlich wie andere 68Ga-markierte Somatostatinrezeptorliganden. Nach einer Injektion von OPS202, das mit 68Ga markiert wurde, wurden die höchsten Energiedosen in der Harnblase (0.10 mGy/MBq) und den Nieren (0.84 mGy/MBq) beobachtet. Der berechnete mittlere effektive Dosiskoeffizienten von Patienten, die mit 68Ga-OPS202 injiziert wurden, betrug 0.024 mSv/MBq (3.6 mSv für 150 MBq 68Ga-OPS202), ähnlich wie bei anderen 68Ga-markierten Verbindungen. Basierend auf den biokinetischen und dosimetrischen Untersuchungen von OPS201 wird nach der Injektion von 177Lu-OPS201 in der ersten Phase (Halbwertszeit: 1.83 h) für jede Spezies eine schnelle Ausscheidung der Verbindung beobachtet. 10 Minuten nach der Injektion zirkulieren weniger als 5% der injizierten Aktivität pro Milliliter Blut bei Schweinen und Menschen. Die Analyse der Daten von Mäusen, Schweinen und vorläufigen Patienten liefert Hinweise darauf, dass Patienten, die in eine 177Lu-OPS201-Studie aufgenommen werden, nicht dem Risiko für eine Überexposition ausgesetzt wären. Basierend auf unseren Ergebnissen werden für 177Lu markierte Studien Nachbeobachtungszeiten insbesondere zu späten Zeitpunkten (mehr als 72 h) für die Berechnungen des zeitintegrierten Aktivitätskoeffizienten (TIAC) benötigt, um die Fläche unter der Kurve angemessen darzustellen und sowohl die Biokinetik als auch die Dosimetrie genau zu analysieren. Späte Zeitpunkte (nach 72 h) haben einen großen Einfluss auf die Berechnung der Energiedosis. Darüber hinaus wurden mehrere Extrapolationsmethoden vom Tier auf den Menschen getestet, um die geeignetsten Extrapolationsmethoden zu finden, die die Unterschiede zwischen den verschiedenen Spezies von Dosimetrie-Daten minimieren. Für OPS201 ergibt die Zeitskalierung oder die Kombination von relativer Masse und Zeitskalierung die ähnlichsten TIAC-Werte, wenn die Organmassenverhältnisse zwischen den Spezies hoch sind. Bei der Zeitskalierung wird die Scan-/Samplingzeit durch das Verhältnis der Ganzkörpermassen der jeweiligen Spezies skaliert. Bei der relativen Massenskalierung werden die TIACs basierend auf dem Verhältnis der Ganzkörper- und Organmasse der jeweiligen Spezies skaliert. Andere getestete Methoden zeigten höhere Abweichungen. Um den Einfluss der Bildquantifizierung und die Wahl der optimalen Scanzeitpunkte zu untersuchen, wurde eine Studie in einem Schweinemodell, die in Zusammenarbeit mit der Universität Aalborg und der Octreopharm Sciences GmbH durchgeführt wurde, neu analysiert. Da die Nieren bei PRRT mit 177Lu markierten Peptiden Risikoorgane sind, wurden mehrere Quantifizierungsmethoden ausgewählt, die auf 2D- und 3D-Bildgebung basieren. Zu diesem Zweck wurde ein 3D gedrucktes Schweine-Nierenphantom vorbereitet und, mit und ohne Hintergrundaktivitäten, die den Aktivitäten in den Schweinescans entsprechen, gemessen und quantifiziert,. Dosimetrie-Daten, die aus dem Schweinescan basierend auf mehreren 3D-Bildern und basierend auf mehreren 2D-Planarbildern in Kombination mit einem SPECT/CT-Bild („MP1S-Imaging“) gewonnen wurden, wurden mit den Ergebnissen der Phantomscans verglichen. Die so ermittelten TIACs des Phantoms mit Hintergrund, basierend auf beiden Bildgebungstechniken, entsprachen in etwa den Ergebnissen derjenigen Schweinedaten, die auf mehrfachen SPECT/CT-Aufnahmen basierten. Um die Auswirkungen der späten Zeitpunkte auf die Dosimetrie und die Werte der Energiedosen in 177Lu Therapien zu untersuchen, wurde außerdem der Unterschied, der mit der Eliminierung der späten zwei Scanzeitpunkte verbunden ist, auf die TIACs analysiert. Wenn auf mehreren SPECT/CT- und Hybrid-Bildern basierten TIACs des Schweins untersucht wurden, war die berechnete TIAC (einschließlich aller Zeitpunkte) basierend auf mehreren SPECT/CT-Bildern im Vergleich zur Hybrid Imaging um den Faktor 1.4 höher. Durch die Eliminierung von späten Zeitpunkten aus der erstellten Zeitaktivitätskurve erhöht sich der TIAC um den Faktor 2.4 mit entsprechend höheren TIAC Unsicherheiten. Daher ist zu folgern, dass eine weitere Evaluierung von 68Ga-OPS202 für die PET/CT-Bildgebung und 177Lu-OPS201 für die Behandlung von NET-Patienten erforderlich ist. Insbesondere wäre ein direkter Vergleich von Agonisten und OPS-Peptiden in Bezug auf Biokinetik, Biodistribution und Dosimetrie hilfreich. Darüber hinaus bedarf der Einfluss der späten Zeitpunkte bei Dosimetrie-Scans weiterer Aufmerksamkeit, insbesondere bei der Nierendosimetrie.

Published
2021

10. In Vivo Biokinetics of 177Lu-OPS201 in Mice and Pigs as a Model for Predicting Human Dosimetry

Author

Beykan, Seval, Fani, Melpomeni, Jensen, Svend Borup, Nicolas, Guillaume, Wild, Damian, Kaufmann, Jens, and Lassmann, Michael

Subjects
Male, Radioisotopes, lcsh:Medical technology, Article Subject, Swine, Lutetium, In Vivo Dosimetry, Kidney, Mice, lcsh:R855-855.5, Liver, Organometallic Compounds, Animals, Humans, Female, ddc:610, Receptors, Somatostatin, Research Article
Abstract

Introduction. 177 Lu-OPS201 is a high-affinity somatostatin receptor subtype 2 antagonist for PRRT in patients with neuroendocrine tumors. The aim is to find the optimal scaling for dosimetry and to compare the biokinetics of 177 Lu-OPS201 in animals and humans. Methods. Data on biokinetics of 177 Lu-OPS201 were analyzed in athymic nude Foxn1 nu mice (28 F, weight: 26 ± 1 g), Danish Landrace pigs (3 F-1 M, weight: 28 ± 2 kg), and patients (3 F-1 M, weight: 61 ± 17 kg) with administered activities of 0.19–0.27 MBq (mice), 97–113 MBq (pigs), and 850–1086 MBq (patients). After euthanizing mice (up to 168 h), the organ-specific activity contents (including blood) were measured. Multiple planar and SPECT/CT scans were performed until 250 h (pigs) and 72 h (patients) to quantify the uptake in the kidneys and liver. Blood samples were taken up to 23 h (patients) and 300 h (pigs). In pigs and patients, kidney protection was applied. Time-dependent uptake data sets were created for each species and organ/tissue. Biexponential fits were applied to compare the biokinetics in the kidneys, liver, and blood of each species. The time-integrated activity coefficients (TIACs) were calculated by using NUKFIT. To determine the optimal scaling, several methods (relative mass scaling, time scaling, combined mass and time scaling, and allometric scaling) were compared. Results. A fast blood clearance of the compound was observed in the first phase (

Published
2019

12. Safety, Biodistribution, and Radiation Dosimetry of Ga-OPS202 in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Prospective Phase I Imaging Study

Author

Nicolas, Guillaume P, Beykan, Seval, Bouterfa, Hakim, Kaufmann, Jens, Bauman, Andreas, Lassmann, Michael, Reubi, Jean Claude, Rivier, Jean E F, Maecke, Helmut R, Fani, Melpomeni, and Wild, Damian

Subjects
570 Life sciences, biology, 610 Medicine & health
Abstract

Preclinical and preliminary clinical evidence indicates that radiolabeled somatostatin (sst) receptor antagonists perform better than agonists in detecting neuroendocrine tumors (NETs). We performed a prospective phase I/II study to evaluate the sst receptor antagonist Ga-OPS202 (Ga-NODAGA-JR11; NODAGA = 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid and JR11 = Cpa-c(dCys-Aph(Hor)-dAph(Cbm)-Lys-Thr-Cys)-dTyr-NH)) for PET imaging. Here, we report the results of phase I of the study. Patients received 2 single 150-MBq intravenous injections of Ga-OPS202 3-4 wk apart (15 μg of peptide at visit 1 and 50 μg at visit 2). At visit 1, a dynamic PET/CT scan over the kidney was obtained during the first 30 min after injection, and static whole-body scans were obtained at 0.5, 1, 2, and 4 h after injection; at visit 2, a static whole-body scan was obtained at 1 h. Blood samples and urine were collected at regular intervals to determine Ga-OPS202 pharmacokinetics. Safety, biodistribution, radiation dosimetry, and the most appropriate imaging time point for Ga-OPS202 were assessed. Twelve patients with well-differentiated gastroenteropancreatic (GEP) NETs took part in the study. Ga-OPS202 cleared rapidly from the blood, with a mean residence time of 2.4 ± 1.1 min/L. The organs with the highest mean dose coefficients were the urinary bladder wall, kidneys, and spleen. The calculated effective dose was 2.4E-02 ± 0.2E-02 mSv/MBq, corresponding to 3.6 mSv, for a reference activity of 150 MBq. Based on total numbers of detected malignant lesions, the optimal time window for the scan was between 1 and 2 h. For malignant liver lesions, the time point at which most patients had the highest mean tumor contrast was 1 h. Ga-OPS202 was well tolerated; adverse events were grade 1 or 2, and there were no signals of concern from laboratory blood or urinalysis tests. Ga-OPS202 showed favorable biodistribution and imaging properties, with optimal tumor contrast between 1 and 2 h after injection. Dosimetry analysis revealed that the dose delivered by Ga-OPS202 to organs is similar to that delivered by other Ga-labeled sst analogs. Further evaluation of Ga-OPS202 for PET/CT imaging of NETs is therefore warranted.

Published
2018
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14. Microscale radiosynthesis, preclinical imaging and dosimetry study of [18F]AMBF3-TATE: A potential PET tracer for clinical imaging of somatostatin receptors

Author

Lisova, Ksenia, primary, Sergeev, Maxim, additional, Evans-Axelsson, Susan, additional, Stuparu, Andreea D., additional, Beykan, Seval, additional, Collins, Jeffrey, additional, Jones, Jason, additional, Lassmann, Michael, additional, Herrmann, Ken, additional, Perrin, David, additional, Lee, Jason T., additional, Slavik, Roger, additional, and van Dam, R. Michael, additional

Published
2018
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17. 177Lu-OPS201 targeting somatostatin receptors:in vivo biodistribution and dosimetry in a pig model

Author

Beykan, Seval, Dam, Jan S., Eberlein, Uta, Kaufmann, Jens, Kjærgaard, Benedict, Jødal, Lars, Bouterfa, Hakim, Bejot, Romain, Lassmann, Michael, and Jensen, Svend Borup

Subjects
Journal Article, ddc:610
Abstract

Background \(^{177}\)Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of \(^{177}\)Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications. Results \(^{177}\)Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq \(^{177}\)Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of 177Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels. Conclusions The \(^{177}\)Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.

Published
2016

18. Safety, Biodistribution, and Radiation Dosimetry of 68Ga-OPS202 in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Prospective Phase I Imaging Study

Author

Nicolas, Guillaume P., primary, Beykan, Seval, additional, Bouterfa, Hakim, additional, Kaufmann, Jens, additional, Bauman, Andreas, additional, Lassmann, Michael, additional, Reubi, Jean Claude, additional, Rivier, Jean E.F., additional, Maecke, Helmut R., additional, Fani, Melpomeni, additional, and Wild, Damian, additional

Published
2017
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19. [177Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent

Author

Schottelius, Margret, primary, Osl, Theresa, additional, Poschenrieder, Andreas, additional, Hoffmann, Frauke, additional, Beykan, Seval, additional, Hänscheid, Heribert, additional, Schirbel, Andreas, additional, Buck, Andreas K., additional, Kropf, Saskia, additional, Schwaiger, Markus, additional, Keller, Ulrich, additional, Lassmann, Michael, additional, and Wester, Hans-Jürgen, additional

Published
2017
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20. In Vivo Biokinetics of 177Lu-OPS201 in Mice and Pigs as a Model for Predicting Human Dosimetry.

Author

Beykan, Seval, Fani, Melpomeni, Jensen, Svend Borup, Nicolas, Guillaume, Wild, Damian, Kaufmann, Jens, and Lassmann, Michael

Abstract

Introduction. 177Lu-OPS201 is a high-affinity somatostatin receptor subtype 2 antagonist for PRRT in patients with neuroendocrine tumors. The aim is to find the optimal scaling for dosimetry and to compare the biokinetics of 177Lu-OPS201 in animals and humans. Methods. Data on biokinetics of 177Lu-OPS201 were analyzed in athymic nude Foxn1nu mice (28 F, weight: 26 ± 1 g), Danish Landrace pigs (3 F-1 M, weight: 28 ± 2 kg), and patients (3 F-1 M, weight: 61 ± 17 kg) with administered activities of 0.19–0.27 MBq (mice), 97–113 MBq (pigs), and 850–1086 MBq (patients). After euthanizing mice (up to 168 h), the organ-specific activity contents (including blood) were measured. Multiple planar and SPECT/CT scans were performed until 250 h (pigs) and 72 h (patients) to quantify the uptake in the kidneys and liver. Blood samples were taken up to 23 h (patients) and 300 h (pigs). In pigs and patients, kidney protection was applied. Time-dependent uptake data sets were created for each species and organ/tissue. Biexponential fits were applied to compare the biokinetics in the kidneys, liver, and blood of each species. The time-integrated activity coefficients (TIACs) were calculated by using NUKFIT. To determine the optimal scaling, several methods (relative mass scaling, time scaling, combined mass and time scaling, and allometric scaling) were compared. Results. A fast blood clearance of the compound was observed in the first phase (<56 h) for all species. In comparison with patients, pigs showed higher liver retention. Based on the direct comparison of the TIACs, an underestimation in mice (liver and kidneys) and an overestimation in pigs' kidneys compared to the patient data (kidney TIAC: mice = 1.4 h, pigs = 7.7 h, and patients = 5.8 h; liver TIAC: mice = 0.7 h, pigs = 4.1 h, and patients = 5.3 h) were observed. Most similar TIACs were obtained by applying time scaling (mice) and combined scaling (pigs) (kidney TIAC: mice = 3.9 h, pigs = 4.8 h, and patients = 5.8 h; liver TIAC: mice = 0.9 h, pigs = 4.7 h, and patients = 5.3 h). Conclusion. If the organ mass ratios between the species are high, the combined mass and time scaling method is optimal to minimize the interspecies differences. The analysis of the fit functions and the TIACs shows that pigs are better mimicking human biokinetics. [ABSTRACT FROM AUTHOR]

Published
2019
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21. The impact of 177Lu-octreotide therapy on 99mTc-MAG3 clearance is not predictive for late nephropathy

Author

Werner, Rudolf A., primary, Beykan, Seval, additional, Higuchi, Takahiro, additional, Lückerath, Katharina, additional, Weich, Alexander, additional, Scheurlen, Michael, additional, Bluemel, Christina, additional, Herrmann, Ken, additional, Buck, Andreas K., additional, Lassmann, Michael, additional, Lapa, Constantin, additional, and Hänscheid, Heribert, additional

Published
2016
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23. 68Ga- and 177Lu-Labeled PSMA I&T: Optimization of a PSMA-Targeted Theranostic Concept and First Proof-of-Concept Human Studies

Author

Weineisen, Martina, primary, Schottelius, Margret, additional, Simecek, Jakub, additional, Baum, Richard P., additional, Yildiz, Akin, additional, Beykan, Seval, additional, Kulkarni, Harshad R., additional, Lassmann, Michael, additional, Klette, Ingo, additional, Eiber, Matthias, additional, Schwaiger, Markus, additional, and Wester, Hans-Jürgen, additional

Published
2015
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24. Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model.

Author

Beykan, Seval, Dam, Jan, Eberlein, Uta, Kaufmann, Jens, Kjærgaard, Benedict, Jødal, Lars, Bouterfa, Hakim, Bejot, Romain, Lassmann, Michael, and Jensen, Svend

Subjects
*NEUROENDOCRINE tumors, *RADIATION dosimetry, *LUTETIUM, *SOMATOSTATIN, *LABORATORY swine, *PEPTIDE receptors, *RADIOISOTOPE therapy, *THERAPEUTICS
Abstract

Background: Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications. Results: Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels. Conclusions: The Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range. [ABSTRACT FROM AUTHOR]

Published
2016
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26. Nöroendokrin Tümörlü (NET) Hastalar için Hastaya Özgün Lu-177-DOTATATE Tedavi Aktivitesinin Optimize Edilmesi.

Author

Beykan, Seval, Yaylalı, Olga, Yüksel, Doğangün, Buldu, Gamze Ergiyen, Nacar, Berfu, Gültekin, Aziz, Şengöz, Tarık, Lassmann, Michael, and Karaaslan, İpek

Abstract

Amaç: Birincil amaç, Nöroendokrin tümör (NET) hastalarında hastaya özgün Lu-177-DOTATATE tutulumunu araştırmak ve dozimetreye dayalı tedavi analizi yapmaktır. Ayrıca, tedavi siklüslerinde ve sonrasında (peri/post-tedavi), yüksek riskli organ olan böbreklerde absorbe edilen dozları hesaplayarak organa dayalı böbrek dozimetrisi yapmaktır. Peri-tedavi böbrek biyokinetiği ve Lu-177-DOTATATE dağılımına bağlı, Lu-177- DOTATATE bağlanma etkinliğini analizi de ayrıca araştırıldı. Bunlara ek olarak, böbreklere Gy-23 doz sınırını geçmeden, hastaya özgün dozimetri sonucuna göre, maximum gerekli tedavi aktivitesini hesaplandı. Yöntem: Ampirik (6,5-7,4 GBq) Lu-177-DOTATATE tedavisi uygulanan 11 NET hastası, Lu-177-DOTATATE için oluşturulan spesifik görüntüleme protokolüne dahil edildi. Hastalara Lu-177-DOTATATE enjeksiyon öncesinde başlanan ve 4 saat devam eden amino-acid infusionu verildi. Hastalardan 24. saat tek foton emisyon bilgisayarlı tomografi (SPECT)/bilgisayarlı tomografi (BT) ve çoklu tüm-vücut planar görüntülemeleri (150. saate dek) alındı. Böbrekler ve seçilen tümörlerde zaman aktivite eğrileri oluşturulup, zamanla uyumlu aktivite katsayıları (TIACs), NUKFIT yazılımı kullanılarak hesaplandı. Hesaplanan organ-TIAC değerleri kullanılarak, hastaya özgün böbrek absorbe dozları OLINDA/EXM ve IDAC-Dose 2.1 yazılım programları ile hesaplandı. Bulgular: OLINDA ve IDAC-Dose 2,1'e dayalı hastaya özgün böbrek absorbe doz değerleri 5,7-13 Gy olarak hesaplandı. Hastaya özgün böbrek TACs analizine göre, Lu-177-DOTATATE tutulumunun her bir tedavi siklüsünde değişiklik gösterdiği saptanmış olup hastaya özgün tedavi protokolünün önemini göstermektedir. Tedavi sonrası, karaciğerdeki tümör hacimlerinin, 3/11 hasta (%20-40 arasında) azaldığı, 6/11 hastada sabit kaldığı, 2/11 hastada artış olduğu saptandı. Eğer tedavi, Gy-23 böbrek dozu aşılmaxızın, mümkün olan maksimum aktivite miktarı ile yapılsaydı, 22,3 GBq177-Lu- DOTATATE tedavi aktivitesi olarak hastalara güvenle enjekte edilebilirdi. Sonuç: Bu çalışmanın önemi Türkiye'de 177-Lu-DOTATATE tedavisi uygulanan NET hastalarının voxel bazlı ilk organ dozimetri verilerini içermesidir. Ayrıca, Türkiye'de yapılan Lu-177-DOTATATE'ın böbreklere ve tümörlere bağlanma özelliklerini araştıran ilk çalışmadır. Her tedavi siklüsünde böbreklerde tutulumunun değişmesi, tümör dokularının regresyon/progresyonu veya reseptör bağlanma değişiklikleri nedeni ile olabileceği düşünülmektedir. Ampirik tedavi yerine, dozimetri ve biyokinetik analizlere dayanan, böbreklere Gy-23 sınırını geçmeden, hastaya özgün pre-dozimetri sonucuna göre, spesifik tedavi protokolü uygulandığında, tümör dokusuna daha yüksek doz verilebileceği ve daha iyi tedavi yanıtları alınabileceği düşünülmektedir. [ABSTRACT FROM AUTHOR]

Published
2020

27. Patient-Specific Dosimetry of Lu-177-DOTATATE Peptide Receptor Radionuclide Therapy With High Activities.

Author

Beykan, Seval, Eberlein, Uta, Werner, Rudolf, Lapa, Constantin, Buck, Andreas, Kudlich, Theodor, and Lassmann, Michael

Subjects
*RADIATION dosimetry, *NEUROENDOCRINE tumors, *RADIOISOTOPES, *BLOOD volume, *BONE marrow, *ABSORBED dose
Abstract

Objectives: The aim is to analyze post-therapeutical dosimetry of three patients with neuroendocrine tumors treated with high activities of Lu- 177-DOTATATE and to compare the results of three software used for calculating the absorbed dose to the kidneys. In addition, the blood-based and image-based techniques applied to estimate bone marrow absorbed doses were analyzed. Methods: Multiple blood samples (up to 96h), 24h SPECT/CT data and several whole-body planar images (up to 95h) were acquired after an administered therapy activity of 14.4-19.3 GBq. The administered activities were chosen based on pre-dosimetry kidney absorbed dose coefficients obtained without kidney protection with the aim not to exceed a kidney absorbed dose of 23Gy after a single administration of Lu-177-DOTATATE (170-237 MBq). Time-activity curves and the corresponding timeintegrated activity coefficients for kidneys, blood, whole-body and lumbar vertebrae 2-4 (representing bone marrow) were calculated. Based on these data, patient-specific kidney absorbed dose coefficients were obtained with NUKDOS, OLINDA1.1 and IDAC-Dose 2.1. Image-ased and blood-based bone marrow absorbed doses were analyzed and compared. Results: In blood we observed lower than 8% of the injected activity 2h after injection (assuming a blood volume of 5.3 liter). Compared to the standard therapy (7.4 GBq) the absorbed dose to the blood after 48 h is higher (mean: 186±54 mGy vs. 79±16 mGy). Image-based (NUKDOS) and blood-based bone marrow absorbed doses ranged from 0.3-0.8 Gy (LV2-4- based) and 0.1-0.3 Gy (blood-based), respectively. Patient-specific kidney absorbed dose coefficients and doses were identical for NUKDOS, OLINDA 1.1 and IDAC-Dose 2.1 and well below 23 Gy (Pat 1: 0.7 Gy/GBq, 9.6 Gy; Pat 2: 0.3 Gy/GBq, 4.8 Gy; Pat 3: 0.4 Gy/GBq, 7.0 Gy). Conclusions: This study provides the first post-therapeutic dosimetry data of Lu-177-DOTATATE patients receiving patient-specific higher activities compared to the standard Lu-177-DOTATATE treatment. The results show that high Lu-177-DOTATATE activities can be administered safely based on pre-therapeutic kidney dosimetry. In addition, blood-based bone marrow absorbed doses are by a factor of three lower than image-based bone marrow absorbed doses advocating the use of image-based dosimetry. When using patient-specific kidney masses, OLINDA 1.1 and IDAC-Dose 2.1 results were similar to NUKDOS which uses patient-specific pre-tabulated voxel-based s-values. [ABSTRACT FROM AUTHOR]

Published
2019

28. Patient Dosimetry of Lu-177 DOTATATE Peptide Receptor Radionuclide Therapy with High Activities.

Author

Beykan, Seval, Eberlein, Uta, Werner, Rudolf A., Lapa, Constantin, Buck, Andreas K., Kudlich, Theodor, and Lassmann, Michael

Subjects
*RADIATION dosimetry, *NEUROENDOCRINE tumors, *BONE marrow, *ABSORBED dose, *RADIOPHARMACEUTICALS
Abstract

Objective: The aim of the study is to analyse the pre- and peri-therapeutic dosimetry of patients with neuroendocrine tumors treated with highactivities of Lu-177 DOTATATE. Method: Multiple blood samples (up to 96h for peri-therapeutic dosimetry), 24h SPECT/CT data and a series of WB planar images (up to 95h) were acquired after an injection of Lu-177 DOTATATE for pre- and peri-therapeutic dosimetry of Lu-177 DOTATATE (pre-therapeutic activity range: 170-237 MBq, therapy activity administered: 14, 4GBq-19, 3GBq), time-activity curves (TAC) and the corresponding time-integrated activity coefficients (TIACs) for the kidneys, blood, whole-body and LV2-4 were calculated by integration of the respective TACs with using the software solution NUKDOS. Based on these data, patient specific absorbed organ dose coefficients were calculated for both pre- and peri-therapeutic dosimetry. The administered therapy activity was chosen based on pre-dosimetry data taking the fact into account that no kidney protection was applied pre-therapeutically. In addition, for the therapy, blood based and image based bone marrow absorbed dose values were compared. Results: In blood we observed <8% of the injected activity 2h after injection. Compared to the standard therapy (7, 7GBq) the absorbed dose to the blood after 48 h is higher (mean: 186mGy vs, 78mGy). For pre-therapeutic dosimetry, the absorbed dose values for kidneys were between 0, 3-0, 7Gy, for each patient while the kidney absorbed dose values for the therapy were in the range of 15, 3-17, 4Gy. Image-based and blood-based bone marrow absorbed doses for therapy ranged from 0, 7-1, 4Gy (LV2-4 based) and 0, 1-0, 3Gy (blood based), respectively. Conclusion: This study provides the first pre- and post- dosimetry analyses of Lu-177 DOTATATE patients receiving higher activities compared to the standard Lu-177 DOTATATE treatment. The results of this study show that high Lu-177 DOTATATE can be administered safely based on pre-therapeutic dosimetry. [ABSTRACT FROM AUTHOR]

Published
2018

29. In Vivo Biokinetics of 177 Lu-OPS201 in Mice and Pigs as a Model for Predicting Human Dosimetry.

Author

Beykan S, Fani M, Jensen SB, Nicolas G, Wild D, Kaufmann J, and Lassmann M

Subjects
Animals, Female, Humans, Kidney metabolism, Liver metabolism, Male, Mice, Organometallic Compounds chemistry, Receptors, Somatostatin antagonists & inhibitors, Swine, In Vivo Dosimetry methods, Lutetium analysis, Organometallic Compounds pharmacokinetics, Radioisotopes analysis
Abstract

Introduction: 177 Lu-OPS201 is a high-affinity somatostatin receptor subtype 2 antagonist for PRRT in patients with neuroendocrine tumors. The aim is to find the optimal scaling for dosimetry and to compare the biokinetics of 177 Lu-OPS201 in animals and humans., Methods: Data on biokinetics of 177 Lu-OPS201 were analyzed in athymic nude Foxn1 nu mice (28 F, weight: 26 ± 1 g), Danish Landrace pigs (3 F-1 M, weight: 28 ± 2 kg), and patients (3 F-1 M, weight: 61 ± 17 kg) with administered activities of 0.19-0.27 MBq (mice), 97-113 MBq (pigs), and 850-1086 MBq (patients). After euthanizing mice (up to 168 h), the organ-specific activity contents (including blood) were measured. Multiple planar and SPECT/CT scans were performed until 250 h (pigs) and 72 h (patients) to quantify the uptake in the kidneys and liver. Blood samples were taken up to 23 h (patients) and 300 h (pigs). In pigs and patients, kidney protection was applied. Time-dependent uptake data sets were created for each species and organ/tissue. Biexponential fits were applied to compare the biokinetics in the kidneys, liver, and blood of each species. The time-integrated activity coefficients (TIACs) were calculated by using NUKFIT. To determine the optimal scaling, several methods (relative mass scaling, time scaling, combined mass and time scaling, and allometric scaling) were compared., Results: A fast blood clearance of the compound was observed in the first phase (<56 h) for all species. In comparison with patients, pigs showed higher liver retention. Based on the direct comparison of the TIACs, an underestimation in mice (liver and kidneys) and an overestimation in pigs' kidneys compared to the patient data (kidney TIAC: mice = 1.4 h, pigs = 7.7 h, and patients = 5.8 h; liver TIAC: mice = 0.7 h, pigs = 4.1 h, and patients = 5.3 h) were observed. Most similar TIACs were obtained by applying time scaling (mice) and combined scaling (pigs) (kidney TIAC: mice = 3.9 h, pigs = 4.8 h, and patients = 5.8 h; liver TIAC: mice = 0.9 h, pigs = 4.7 h, and patients = 5.3 h)., Conclusion: If the organ mass ratios between the species are high, the combined mass and time scaling method is optimal to minimize the interspecies differences. The analysis of the fit functions and the TIACs shows that pigs are better mimicking human biokinetics.

Published
2019
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30. Safety, Biodistribution, and Radiation Dosimetry of 68 Ga-OPS202 in Patients with Gastroenteropancreatic Neuroendocrine Tumors: A Prospective Phase I Imaging Study.

Author

Nicolas GP, Beykan S, Bouterfa H, Kaufmann J, Bauman A, Lassmann M, Reubi JC, Rivier JEF, Maecke HR, Fani M, and Wild D

Subjects
Acetates adverse effects, Acetates pharmacology, Female, Heterocyclic Compounds, 1-Ring adverse effects, Heterocyclic Compounds, 1-Ring pharmacology, Humans, Intestinal Neoplasms metabolism, Male, Middle Aged, Neuroendocrine Tumors metabolism, Pancreatic Neoplasms metabolism, Positron-Emission Tomography adverse effects, Radiometry, Receptors, Somatostatin antagonists & inhibitors, Stomach Neoplasms metabolism, Time Factors, Tissue Distribution, Acetates chemistry, Acetates pharmacokinetics, Gallium Radioisotopes, Heterocyclic Compounds, 1-Ring chemistry, Heterocyclic Compounds, 1-Ring pharmacokinetics, Intestinal Neoplasms diagnostic imaging, Neuroendocrine Tumors diagnostic imaging, Oligopeptides chemistry, Pancreatic Neoplasms diagnostic imaging, Positron-Emission Tomography methods, Safety, Stomach Neoplasms diagnostic imaging
Abstract

Preclinical and preliminary clinical evidence indicates that radiolabeled somatostatin (sst) receptor antagonists perform better than agonists in detecting neuroendocrine tumors (NETs). We performed a prospective phase I/II study to evaluate the sst receptor antagonist 68 Ga-OPS202 ( 68 Ga-NODAGA-JR11; NODAGA = 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid and JR11 = Cpa-c(dCys-Aph(Hor)-dAph(Cbm)-Lys-Thr-Cys)-dTyr-NH 2 )) for PET imaging. Here, we report the results of phase I of the study. Methods: Patients received 2 single 150-MBq intravenous injections of 68 Ga-OPS202 3-4 wk apart (15 μg of peptide at visit 1 and 50 μg at visit 2). At visit 1, a dynamic PET/CT scan over the kidney was obtained during the first 30 min after injection, and static whole-body scans were obtained at 0.5, 1, 2, and 4 h after injection; at visit 2, a static whole-body scan was obtained at 1 h. Blood samples and urine were collected at regular intervals to determine 68 Ga-OPS202 pharmacokinetics. Safety, biodistribution, radiation dosimetry, and the most appropriate imaging time point for 68 Ga-OPS202 were assessed. Results: Twelve patients with well-differentiated gastroenteropancreatic (GEP) NETs took part in the study. 68 Ga-OPS202 cleared rapidly from the blood, with a mean residence time of 2.4 ± 1.1 min/L. The organs with the highest mean dose coefficients were the urinary bladder wall, kidneys, and spleen. The calculated effective dose was 2.4E-02 ± 0.2E-02 mSv/MBq, corresponding to 3.6 mSv, for a reference activity of 150 MBq. Based on total numbers of detected malignant lesions, the optimal time window for the scan was between 1 and 2 h. For malignant liver lesions, the time point at which most patients had the highest mean tumor contrast was 1 h. 68 Ga-OPS202 was well tolerated; adverse events were grade 1 or 2, and there were no signals of concern from laboratory blood or urinalysis tests. Conclusion: 68 Ga-OPS202 showed favorable biodistribution and imaging properties, with optimal tumor contrast between 1 and 2 h after injection. Dosimetry analysis revealed that the dose delivered by 68 Ga-OPS202 to organs is similar to that delivered by other 68 Ga-labeled sst analogs. Further evaluation of 68 Ga-OPS202 for PET/CT imaging of NETs is therefore warranted., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Published
2018
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31. Microscale radiosynthesis, preclinical imaging and dosimetry study of [ 18 F]AMBF 3 -TATE: A potential PET tracer for clinical imaging of somatostatin receptors.

Author

Lisova K, Sergeev M, Evans-Axelsson S, Stuparu AD, Beykan S, Collins J, Jones J, Lassmann M, Herrmann K, Perrin D, Lee JT, Slavik R, and van Dam RM

Subjects
Animals, Cell Line, Tumor, Mice, Octreotide chemistry, Radioactive Tracers, Radiometry, Boron Compounds chemistry, Fluorine Radioisotopes, Lab-On-A-Chip Devices, Octreotide analogs & derivatives, Positron Emission Tomography Computed Tomography, Radiochemistry instrumentation, Receptors, Somatostatin metabolism
Abstract

Background: Peptides labeled with positron-emitting isotopes are emerging as a versatile class of compounds for the development of highly specific, targeted imaging agents for diagnostic imaging via positron-emission tomography (PET) and for precision medicine via theranostic applications. Despite the success of peptides labeled with gallium-68 (for imaging) or lutetium-177 (for therapy) in the clinical management of patients with neuroendocrine tumors or prostate cancer, there are significant advantages of using fluorine-18 for imaging. Recent developments have greatly simplified such labeling: in particular, labeling of organotrifluoroborates via isotopic exchange can readily be performed in a single-step under aqueous conditions and without the need for HPLC purification. Though an automated synthesis has not yet been explored, microfluidic approaches have emerged for 18 F-labeling with high speed, minimal reagents, and high molar activity compared to conventional approaches. As a proof-of-concept, we performed microfluidic labeling of an octreotate analog ([ 18 F]AMBF 3 -TATE), a promising 18 F-labeled analog that could compete with [ 68 Ga]Ga-DOTATATE with the advantage of providing a greater number of patient doses per batch produced., Methods: Both [ 18 F]AMBF 3 -TATE and [ 68 Ga]Ga-DOTATATE were labeled, the former by microscale methods adapted from manual labeling, and were imaged in mice bearing human SSTR2-overexpressing, rat SSTR2 wildtype, and SSTR2-negative xenografts. Furthermore, a dosimetry analysis was performed for [ 18 F]AMBF 3 -TATE., Results: The micro-synthesis exhibited highly-repeatable performance with radiochemical conversion of 50 ± 6% (n = 15), overall decay-corrected radiochemical yield of 16 ± 1% (n = 5) in ~40 min, radiochemical purity >99%, and high molar activity. Preclinical imaging with [ 18 F]AMBF 3 -TATE in SSTR2 tumor models correlated well with [ 68 Ga]Ga-DOTATATE. The favorable biodistribution, with the highest tracer accumulation in the bladder followed distantly by gastrointestinal tissues, resulted in 1.26 × 10 -2  mSv/MBq maximal estimated effective dose in human, a value lower than that reported for current clinical 18 F- and 68 Ga-labeled compounds., Conclusions: The combination of novel chemical approaches to 18 F-labeling and microdroplet radiochemistry have the potential to serve as a platform for greatly simplified development and production of 18 F-labeled peptide tracers. Favorable preclinical imaging and dosimetry of [ 18 F]AMBF 3 -TATE, combined with a convenient synthesis, validate this assertion and suggest strong potential for clinical translation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Published
2018
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32. [ 177 Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent.

Author

Schottelius M, Osl T, Poschenrieder A, Hoffmann F, Beykan S, Hänscheid H, Schirbel A, Buck AK, Kropf S, Schwaiger M, Keller U, Lassmann M, and Wester HJ

Subjects
Animals, Antineoplastic Agents administration & dosage, Cell Line, Tumor, Disease Models, Animal, Humans, Lutetium administration & dosage, Mice, SCID, Peptides, Cyclic administration & dosage, Peptides, Cyclic pharmacokinetics, Radioisotopes administration & dosage, Antineoplastic Agents pharmacokinetics, Lutetium pharmacokinetics, Lymphoma drug therapy, Molecular Targeted Therapy methods, Multiple Myeloma drug therapy, Radioisotopes pharmacokinetics, Radiotherapy methods, Receptors, CXCR4 metabolism
Abstract

Purpose: Based on the clinical relevance of the chemokine receptor 4 (CXCR4) as a molecular target in cancer and on the success of [ 68 Ga]pentixafor as an imaging probe for high-contrast visualization of CXCR4-expression, the spectrum of clinical CXCR4-targeting was expanded towards peptide receptor radionuclide therapy (PRRT) by the development of [ 177 Lu]pentixather. Experimental design: CXCR4 affinity, binding specificity, hCXCR4 selectivity and internalization efficiency of [ 177 Lu]pentixather were evaluated using different human and murine cancer cell lines. Biodistribution studies (1, 6, 48, 96h and 7d p.i.) and in vivo metabolite analyses were performed using Daudi-lymphoma bearing SCID mice. Extrapolated organ doses were cross-validated with human dosimetry (pre-therapeutic and during [ 177 Lu]pentixather PRRT) in a patient with multiple myeloma (MM). Results: [ 177 Lu]pentixather binds with high affinity, specificity and selectivity to hCXCR4 and shows excellent in vivo stability. Consequently, and supported by >96% plasma protein binding and a logP=-1.76, delaying whole-body clearance of [ 177 Lu]pentixather, tumor accumulation was high and persistent, both in the Daudi model and the MM patient. Tumor/background ratios (7d p.i.) in mice were 499±202, 33±7, 4.0±0.8 and 116±22 for blood, intestine, kidney and muscle, respectively. In the patient, high tumor/kidney and tumor/liver dose ratios of 3.1 and 6.4 were observed during [ 177 Lu]pentixather PRRT (7.8 GBq), with the kidneys being the dose-limiting organs. Conclusions: [ 177 Lu]pentixather shows excellent in vivo CXCR4-targeting characteristics and a suitable pharmacokinetic profile, leading to high tumor uptake and retention and thus high radiation doses to tumor tissue during PRRT, suggesting high clinical potential of this [ 68 Ga]pentixafor/[ 177 Lu]pentixather based CXCR4-targeted theranostic concept., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Published
2017
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33. Synthesis and preclinical evaluation of an Al 18 F radiofluorinated GLU-UREA-LYS(AHX)-HBED-CC PSMA ligand.

Author

Boschi S, Lee JT, Beykan S, Slavik R, Wei L, Spick C, Eberlein U, Buck AK, Lodi F, Cicoria G, Czernin J, Lassmann M, Fanti S, and Herrmann K

Subjects
Animals, Cell Line, Tumor, Drug Evaluation, Preclinical, Edetic Acid analogs & derivatives, Fluorine Radioisotopes pharmacokinetics, Gallium Isotopes, Gallium Radioisotopes, Isotope Labeling methods, Male, Metabolic Clearance Rate, Mice, Mice, Inbred C57BL, Oligopeptides, Organ Specificity, Organometallic Compounds chemical synthesis, Prostatic Neoplasms diagnostic imaging, Radiation Dosage, Radiopharmaceuticals chemical synthesis, Radiopharmaceuticals pharmacokinetics, Reproducibility of Results, Sensitivity and Specificity, Tissue Distribution, Whole-Body Counting, Antigens, Surface metabolism, Biomarkers, Tumor metabolism, Glutamate Carboxypeptidase II metabolism, Organometallic Compounds pharmacokinetics, Positron-Emission Tomography methods, Prostatic Neoplasms metabolism, Radiation Exposure analysis
Abstract

Purpose: The aim of this study was to synthesize and preclinically evaluate an 18 F-PSMA positron emission tomography (PET) tracer. Prostate-specific membrane antigen (PSMA) specificity, biodistribution, and dosimetry in healthy and tumor-bearing mice were determined., Methods: Several conditions for the labeling of 18 F-PSMA-11 via 18 F-AlF-complexation were screened to study the influence of reaction temperature, peptide amount, ethanol volume, and reaction time. After synthesis optimization, biodistribution and dosimetry studies were performed in C57BL6 mice. For proof of PSMA-specificity, mice were implanted with PSMA-negative (PC3) and PSMA-positive (LNCaP) tumors in contralateral flanks. Static and dynamic microPET/computed tomography (CT) imaging was performed., Results: Quantitative labeling yields could be achieved with >97 % radiochemical purity. The 18 F-PSMA-11 uptake was more than 24-fold higher in PSMA-high LNCaP than in PSMA-low PC3 tumors (18.4 ± 3.3 %ID/g and 0.795 ± 0.260 %ID/g, respectively; p < 4.2e-5). Results were confirmed by ex vivo gamma counter analysis of tissues after the last imaging time point. The highest absorbed dose was reported for the kidneys. The maximum effective dose for an administered activity of 200 MBq was 1.72 mSv., Conclusion: 18 F-PSMA-11 using direct labeling of chelate-attached peptide with aluminum-fluoride detected PSMA-expressing tumors with high tumor-to-liver ratios. The kidneys were the dose-limiting organs. Even by applying the most stringent dosimetric calculations, injected activities of up to 0.56 GBq are feasible., Competing Interests: Johannes Czernin is founder of Sofie Biosciences, which manufactures the Genisys4 scanner used in this manuscript. No other potential conflicts of interest are reported.

Published
2016
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