Journal: The Journal of Nuclear Medicine

Abbreviation

J Nucl Med

Publisher

Society of Nuclear Medicine

Journal Volumes

ISSN

0097-9058
0022-3123
0161-5505
2159-662X
1535-5667

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Publications1 - 10 of 62
  • Imaging of Tumor Angiogenesis Using 99mTc-Labeled Human Recombinant Anti-ED-B Fibronectin Antibody Fragments
    Item type: Journal Article
    Berndorff, Dietmar; Borkowski, Sandra; Moosmayer, Dieter; et al. (2006)
    The Journal of Nuclear Medicine
  • Succinylated Gelatin Improves the Theranostic Potential of Radiolabeled Exendin-4 in Insulinoma Patients
    Item type: Journal Article
    Buitinga, Mijke; Jansen, Tom; van der Kroon, Inge; et al. (2019)
    The Journal of Nuclear Medicine
  • Preclinical Evaluation of Benzazepine-Based PET Radioligands (R)- and (S)-¹¹C-Me-NB1 Reveals Distinct Enantiomeric Binding Patterns and a Tightrope Walk Between GluN2B- and σ₁-Receptor–Targeted PET Imaging
    Item type: Journal Article
    Haider, Ahmed; Müller Herde, Adrienne; Krämer, Stefanie-Dorothea; et al. (2019)
    The Journal of Nuclear Medicine
    The study aims to investigate the performance characteristics of the enantiomers of 11C-Me-NB1, a recently reported PET imaging probe that targets the GluN2B subunit of N-methyl-d-aspartate (NMDA) receptors. Methods: Reference compound Me-NB1 (inhibition constant for hGluN1/GluN2B, 5.4 nM) and the phenolic precursor were prepared via multistep synthesis. Following chiral resolution by high-performance liquid chromatography, enantiopure precursor compounds, (R)-NB1 and (S)-NB1, were labeled with 11C and validated in rodents using in vitro/ex vivo autoradiography, PET experiments, and dose–response studies. To illustrate the translational relevance, (R)-11C-Me-NB1 was validated in autoradiographic studies using postmortem human GluN2B-rich cortical and GluN2B-deficient cerebellar brain slices. To determine target engagement, receptor occupancy was assessed at different plasma concentrations of CP101,606, a GluN2B receptor antagonist. Results: The radiosynthesis of (R)- and (S)-11C-Me-NB1 was accomplished in 42% ± 9% (decay-corrected) radiochemical yields. Molar activity ranged from 40 to 336 GBq/μmol, and an excellent radiochemical purity of greater than 99% was achieved. Although (R)-11C-Me-NB1 displayed heterogeneous accumulation with high selectivity for the GluN2B-rich forebrain, (S)-11C-Me-NB1 revealed a homogeneous distribution across all brain regions in rodent brain autoradiograms and predominantly exhibited σ1-receptor binding. Similar to rodent brain, (R)-11C-Me-NB1 showed in postmortem human brain tissues higher binding in the cortex than in the cerebellum. Coincubation of the GluN2B-antagonist CERC-301 (1 μM) reduced cortical but not cerebellar binding, demonstrating the specificity of (R)-11C-Me-NB1 binding to the human GluN2B-containing NMDA receptor. In vivo specificity of (R)-11C-Me-NB1 in the GluN2B-expressing cortex, striatum, thalamus, and hippocampus was demonstrated by PET imaging in rodents. Applying GluN2B-antagonist eliprodil, an evident dose–response behavior was observed with (R)-11C-Me-NB1 but not with (S)-11C-Me-NB1. Our findings further underline the tightrope walk between GluN2B- and σ1-receptor–targeted imaging, illustrated by the entirely different receptor binding behavior of the 2 radioligand enantiomers. Conclusion: (R)-11C-Me-NB1 is a highly selective and specific PET radioligand for imaging the GluN2B subunit of the NMDA receptor. The entirely different receptor binding behavior of (R)-11C-Me-NB1 and (S)-11C-Me-NB1 raises awareness of a delicate balance that is underlying the selective targeting of either GluN2B-carrying NMDA or σ1-receptors.
  • A New F-18-Labeled Folic Acid Derivative with Improved Properties for the PET Imaging of Folate Receptor Positive Tumors
    Item type: Journal Article
    Ross, Tobias L.; Honer, Michael; Mueller, Cristina; et al. (2010)
    The Journal of Nuclear Medicine
  • Tumor-Targeted Interleukin 2 Boosts the Anticancer Activity of FAP-Directed Radioligand Therapeutics
    Item type: Journal Article
    Galbiati, Andrea; Dorten, Paulina; Gilardoni, Ettore; et al. (2023)
    The Journal of Nuclear Medicine
    We studied the antitumor efficacy of a combination of ¹⁷⁷Lu-labeled radioligand therapeutics targeting the fibroblast activation protein (FAP) (OncoFAP and BiOncoFAP) with the antibody–cytokine fusion protein L19-interleukin 2 (L19-IL2) providing targeted delivery of interleukin 2 to tumors. Methods: The biodistribution of ¹⁷⁷Lu-OncoFAP and ¹⁷⁷Lu-BiOncoFAP at different molar amounts (3 vs. 250 nmol/kg) of injected ligand was studied via SPECT/CT in mice bearing subcutaneous HT-1080.hFAP tumors, and self-absorbed tumor and organ doses were calculated. The in vivo anticancer effect of 5 MBq of the radiolabeled preparations was evaluated as monotherapy or in combination with L19-IL2 in subcutaneously implanted HT-1080.hFAP and SK-RC-52.hFAP tumors. Tumor samples from animals treated with ¹⁷⁷Lu-BiOncoFAP, L19-IL2, or both were analyzed by mass spectrometry–based proteomics to identify therapeutic signatures on cellular and stromal markers of cancer and on immunomodulatory targets. Results: ¹⁷⁷Lu-BiOncoFAP led to a significantly higher self-absorbed dose in FAP-positive tumors (0.293 ± 0.123 Gy/MBq) than did ¹⁷⁷Lu-OncoFAP (0.157 ± 0.047 Gy/MBq, P = 0.01) and demonstrated favorable tumor-to-organ ratios at high molar amounts of injected ligand. Administration of L19-IL2 or ¹⁷⁷Lu-BiOncoFAP as single agents led to cancer cures in only a limited number of treated animals. In ¹⁷⁷Lu-BiOncoFAP–plus–L19-IL2 combination therapy, complete remissions were observed in all injected mice (7/7 complete remissions for the HT-1080.hFAP model, and 4/4 complete remissions for the SK-RC-52.hFAP model), suggesting therapeutic synergy. Proteomic studies revealed a mechanism of action based on the activation of natural killer cells, with a significant enhancement of the expression of granzymes and perforin 1 in the tumor microenvironment after combination treatment. Conclusion: The combination of OncoFAP-based radioligand therapeutics with concurrent targeting of interleukin 2 shows synergistic anticancer effects in the treatment of FAP-positive tumors. This experimental finding should be corroborated by future clinical studies.
  • Evaluation of the Metabotropic Glutamate Receptor Subtype 5 Using PET and 11C-ABP688
    Item type: Journal Article
    Treyer, Valerie; Streffer, Johannes; Wyss, Matthias T.; et al. (2007)
    The Journal of Nuclear Medicine
  • Preclinical Development of 18F-OF-NB1 for Imaging GluN2B-Containing N-Methyl-D-Aspartate Receptors and its Utility as a Biomarker for Amyotrophic Lateral Sclerosis
    Item type: Journal Article
    Ahmed, Hazem; Wallimann, Rahel; Haider, Ahmed; et al. (2021)
    The Journal of Nuclear Medicine
    As part of our continuous efforts to develop a suitable fluorine-18 labeled positron emission tomography (PET) radioligand with improved imaging characteristics for imaging the GluN2B-bearing N-Methyl-D-aspartate receptors (NMDARs), we investigated in the current work ortho- and meta-fluorinated analogues of 18F-PF-NB1, a 3-benzazepine-based radiofluorinated probe. Methods: OF-NB1 and MF-NB1 were prepared using a multi-step synthesis and their binding affinities towards GluN2B subunits and selectivity over sigma-1 receptors (σ1Rs) were determined via competitive binding assays. 18F-OF-NB1 was synthesized via copper-mediated radiofluorination, and was evaluated in Wistar rats by in vitro autoradiography, PET imaging, ex vivo biodistribution, metabolite experiments and receptor occupancy studies using CP-101,606, an established GluN2B antagonist. To determine in vivo selectivity, 18F-OF-NB1 was validated in wild-type and σ1R knock-out mice. Translational relevance was assessed in autoradiographic studies using postmortem human brain tissues from healthy individuals and ALS patients, the results of which were corroborated by immunohistochemistry. Results: The binding affinity values for OF-NB1 and MF-NB1 towards the GluN2B subunits were 10.4 ± 4.7 nM and 590 ± 36 nM, respectively. For σ1R binding, OF-NB1 and MF-NB1 exhibited Ki values of 410 nM and 2700 nM, respectively. OF-NB1, which outperformed MF-NB1, was radiolabeled with 18F to afford 18F-OF-NB1 in > 95% radiochemical purity and molar activities of 192±33 GBq/μmol. In autoradiography experiments, 18F-OF-NB1 displayed a heterogeneous and specific binding in GluN2B subunit-rich brain regions such as the cortex, striatum, hypothalamus and hippocampus. PET imaging studies in Wistar rats showed a similar heterogeneous uptake, and no brain radiometabolites were detected. A dose-dependent blocking effect was observed with CP-101,606 (0.5-15 mg/kg) and resulted in a D50 of 8.1 µmol/kg. Postmortem autoradiography results revealed a lower expression level of the GluN2B subunits in ALS brain tissue sections compared to healthy controls, in line with immunohistochemistry results. Conclusion: 18F-OF-NB1 is a highly promising PET imaging probe for imaging the GluN2B subunits of the NMDAR. It possesses utility for receptor occupancy studies and has potential for PET imaging studies in ALS patients and possibly other brain disorders.
  • 5-(2-¹⁸F-Fluoroethoxy)-L-tryptophan as a substrate of system L transport for tumor imaging by PET
    Item type: Journal Article
    Krämer, Stefanie-Dorothea; Mu, Linjing; Müller Herde, Adrienne; et al. (2012)
    The Journal of Nuclear Medicine
    Large neutral l-amino acids are substrates of system L amino acid transporters. The level of one of these, LAT1, is increased in many tumors. Aromatic l-amino acids may also be substrates of aromatic l-amino acid decarboxylase (AADC), the level of which is enhanced in endocrine tumors. Increased amino acid uptake and subsequent decarboxylation result in the intracellular accumulation of the amino acid and its decarboxylation product. (18)F- and (11)C-labeled neutral aromatic amino acids, such as l-3,4-dihydroxy-6-(18)F-fluorophenylalanine ((18)F-FDOPA) and 5-hydroxy-l-[beta-(11)C]tryptophan, are thus successfully used in PET to image endocrine tumors. However, 5-hydroxy-l-[beta-(11)C]tryptophan has a relatively short physical half-life (20 min). In this work, we evaluated the in vitro and in vivo characteristics of the (18)F-labeled tryptophan analog 5-(2-(18)F-fluoroethoxy)-l-tryptophan ((18)F-l-FEHTP) as a PET probe for tumor imaging. METHODS: (18)F-l-FEHTP was synthesized by no-carrier-added (18)F fluorination of 5-hydroxy-l-tryptophan. In vitro cell uptake and efflux of (18)F-l-FEHTP and (18)F-FDOPA were studied with NCI-H69 endocrine small cell lung cancer cells, PC-3 pseudoendocrine prostate cancer cells, and MDA-MB-231 exocrine breast cancer cells. Small-animal PET was performed with the respective xenograft-bearing mice. Tissues were analyzed for potential metabolites. RESULTS: (18)F-l-FEHTP specific activity and radiochemical purity were 50-150 GBq/mumol and greater than 95%, respectively. In vitro cell uptake of (18)F-l-FEHTP was between 48% and 113% of added radioactivity per milligram of protein within 60 min at 37 degrees C and was blocked by greater than 95% in all tested cell lines by the LAT1/2 inhibitor 2-amino-2-norboranecarboxylic acid. (18)F-FDOPA uptake ranged from 26% to 53%/mg. PET studies revealed similar xenograft-to-reference tissue ratios for (18)F-l-FEHTP and (18)F-FDOPA at 30-45 min after injection. In contrast to the (18)F-FDOPA PET results, pretreatment with the AADC inhibitor S-carbidopa did not affect the (18)F-l-FEHTP PET results. No decarboxylation products of (18)F-l-FEHTP were detected in the xenograft homogenates. CONCLUSION: (18)F-l-FEHTP accumulates in endocrine and nonendocrine tumor models via LAT1 transport but is not decarboxylated by AADC. (18)F-l-FEHTP may thus serve as a PET probe for tumor imaging and quantification of tumor LAT1 activity. These findings are of interest in view of the ongoing evaluation of LAT1 substrates and inhibitors for cancer therapy.
  • Dosimetry and first clinical evaluation of the new 18F-radiolabeled bombesin analogue BAY 864367 in patients with prostate cancer
    Item type: Journal Article
    Sah, Bert-Ram; Burger, Irene A.; Schibli, Roger; et al. (2015)
    The Journal of Nuclear Medicine
  • Identification of (R)-[18F]YH134 for Monoacylglycerol Lipase Neuroimaging and Exploration of Its Use for Central Nervous System and Peripheral Drug Development
    Item type: Journal Article
    He, Yingfang; Krämer, Stefanie-Dorothea; Grether, Uwe; et al. (2024)
    The Journal of Nuclear Medicine
    This study aimed to evaluate (R)-[18F]YH134 as a novel PET tracer for imaging monoacylglycerol lipase (MAGL). Considering the ubiquitous expression of MAGL throughout the whole body, the impact of various MAGL inhibitors on (R)-[18F]YH134 brain uptake and its application in brain–periphery crosstalk were explored. Methods: MAGL knockout and wild-type mice were used to evaluate (R)-[18F]YH134 in in vitro autoradiography and PET experiments. To explore the impact of peripheral MAGL occupancy on (R)-[18F]YH134 brain uptake, PET kinetics with an arterial input function were studied in male Wistar rats under baseline and blocking conditions. Results: In in vitro autoradi ography, (R)-[18F]YH134 revealed a heterogeneous distribution pat tern with high binding to MAGL-rich brain regions in wild-type mouse brain slices, whereas the radioactive signal was negligible in MAGL knockout mouse brain slices. The in vivo brain PET images of (R)-[18F]YH134 in wild-type and MAGL knockout mice demonstrated its high specificity and selectivity in mouse brain. A Logan plot with plasma input function was applied to estimate the distribution volume (VT) of (R)-[18F]YH134. VT was significantly reduced by a brain penetrant MAGL inhibitor but was unchanged by a peripherally restricted MAGL inhibitor. The MAGL target occupancy in the periph ery was estimated using (R)-[18F]YH134 PET imaging data from the brain. Conclusion: (R)-[18F]YH134 is a highly specific and selective PET tracer with favorable kinetic properties for imaging MAGL in rodent brain. Our results showed that blocking of the peripheral target influences brain uptake but not the VT of (R)-[18F]YH134. (R)-[18F]YH134 can be used for estimating the dose of MAGL inhibitor at half-maximal peripheral target occupancy.
Publications1 - 10 of 62