Journal: European Journal of Nuclear Medicine and Molecular Imaging

Abbreviation

Eur J Nucl Med Mol Imaging

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Springer

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ISSN

1619-7070
1619-7089

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Publications1 - 10 of 83
  • Role of sex hormones in modulating myocardial perfusion and coronary flow reserve
    Item type: Journal Article
    Haider, Ahmed; Bengs, Susan; Portmann, Angela; et al. (2022)
    European Journal of Nuclear Medicine and Molecular Imaging
    Background A growing body of evidence highlights sex differences in the diagnostic accuracy of cardiovascular imaging modalities. Nonetheless, the role of sex hormones in modulating myocardial perfusion and coronary flow reserve (CFR) is currently unclear. The aim of our study was to assess the impact of female and male sex hormones on myocardial perfusion and CFR. Methods Rest and stress myocardial perfusion imaging (MPI) was conducted by small animal positron emission tomography (PET) with [F-18]flurpiridaz in a total of 56 mice (7-8 months old) including gonadectomized (Gx) and sham-operated males and females, respectively. Myocardial [F-18]flurpiridaz uptake (% injected dose per mL, % ID/mL) was used as a surrogate for myocardial perfusion at rest and following intravenous regadenoson injection, as previously reported. Apparent coronary flow reserve (CFRApp) was calculated as the ratio of stress and rest myocardial perfusion. Left ventricular (LV) morphology and function were assessed by cardiac magnetic resonance (CMR) imaging. Results Orchiectomy resulted in a significant decrease of resting myocardial perfusion (Gx vs. sham, 19.4 +/- 1.0 vs. 22.2 +/- 0.7 % ID/mL, p = 0.034), while myocardial perfusion at stress remained unchanged (Gx vs. sham, 27.5 +/- 1.2 vs. 27.3 +/- 1.2 % ID/mL, p = 0.896). Accordingly, CFRApp was substantially higher in orchiectomized males (Gx vs. sham, 1.43 +/- 0.04 vs. 1.23 +/- 0.05, p = 0.004), and low serum testosterone levels were linked to a blunted resting myocardial perfusion (r = 0.438, p = 0.020) as well as an enhanced CFRApp (r = -0.500, p = 0.007). In contrast, oophorectomy did not affect myocardial perfusion in females. Of note, orchiectomized males showed a reduced LV mass, stroke volume, and left ventricular ejection fraction (LVEF) on CMR, while no such effects were observed in oophorectomized females. Conclusion Our experimental data in mice indicate that sex differences in myocardial perfusion are primarily driven by testosterone. Given the diagnostic importance of PET-MPI in clinical routine, further studies are warranted to determine whether testosterone levels affect the interpretation of myocardial perfusion findings in patients.
  • Preclinical imaging of the co-stimulatory ligands CD80/CD86 with 111In-DOTA-Belatacept in oncology and atherosclerosis
    Item type: Other Conference Item
    Müller Herde, Adrienne; Meletta, Romana; Dennler, Patrick; et al. (2015)
    European Journal of Nuclear Medicine and Molecular Imaging
  • Synthesis, radiolabelling and in vitro/in vivo evaluation of a novel PET ligand for imaging of metabotropic glutamate receptor subtype 5
    Item type: Other Conference Item
    Mu, Linjing; Milicevic Sephton, Selena; Müller, Adrienne; et al. (2012)
    European Journal of Nuclear Medicine and Molecular Imaging
  • Promising potential of [Lu-177]Lu-DOTA-folate to enhance tumor response to immunotherapy-a preclinical study using a syngeneic breast cancer model
    Item type: Journal Article
    Guzik, Patrycja; Siwowska, Klaudia; Fang, Hsin-Yu; et al. (2021)
    European Journal of Nuclear Medicine and Molecular Imaging
    Purpose It was previously demonstrated that radiation effects can enhance the therapy outcome of immune checkpoint inhibitors. In this study, a syngeneic breast tumor mouse model was used to investigate the effect of [Lu-177]Lu-DOTA-folate as an immune stimulus to enhance anti-CTLA-4 immunotherapy. Methods In vitro and in vivo studies were performed to characterize NF9006 breast tumor cells with regard to folate receptor (FR) expression and the possibility of tumor targeting using [Lu-177]Lu-DOTA-folate. A preclinical therapy study was performed over 70 days with NF9006 tumor-bearing mice that received vehicle only (group A); [Lu-177]Lu-DOTA-folate (5 MBq; 3.5 Gy absorbed tumor dose; group B); anti-CTLA-4 antibody (3 x 200 mu g; group C), or both agents (group D). The mice were monitored regarding tumor growth over time and signs indicating adverse events of the treatment. Results [Lu-177]Lu-DOTA-folate bound specifically to NF9006 tumor cells and tissue in vitro and accumulated in NF9006 tumors in vivo. The treatment with [Lu-177]Lu-DOTA-folate or an anti-CTLA-4 antibody had only a minor effect on NF9006 tumor growth and did not substantially increase the median survival time of mice (23 day and 19 days, respectively) as compared with untreated controls (12 days). [Lu-177]Lu-DOTA-folate sensitized, however, the tumors to anti-CTLA-4 immunotherapy, which became obvious by reduced tumor growth and, hence, a significantly improved median survival time of mice (> 70 days). No obvious signs of adverse effects were observed in treated mice as compared with untreated controls. Conclusion Application of [Lu-177]Lu-DOTA-folate had a positive effect on the therapy outcome of anti-CTLA-4 immunotherapy. The results of this study may open new perspectives for future clinical translation of folate radioconjugates.
  • Preclinical evaluation and test-retest studies of [(18)F]PSS232, a novel radioligand for targeting metabotropic glutamate receptor 5 (mGlu5)
    Item type: Journal Article
    Ametamey, Simon M.; Milicevic Sephton, Selena; Müller Herde, Adrienne; et al. (2015)
    European Journal of Nuclear Medicine and Molecular Imaging
    Purpose A novel, 18F-labelled metabotropic glutamate receptor subtype 5 (mGlu5) derivative of [11C]ABP688 ([11C]1), [18F]PSS232 ([18F] ]5), was evaluated in vitro and in vivo for its potential as a PET agent and was used in test–retest reliability studies Methods The radiosynthesis of [18F]5 was accomplished via a one-step reaction using a mesylate precursor. In vitro stability was determined in PBS and plasma, and with liver microsomal enzymes. Metabolite studies were performed using rat brain extracts, blood and urine. In vitro autoradiography was performed on horizontal slices of rat brain using 1 and 8, antagonists for mGlu5 and mGlu1, respectively. Small-animal PET, biodistribution, and test–retest studies were performed in Wistar rats. In vivo, dose-dependent displacement studies were performed using 6 and blocking studies with 7. Results [18F]5 was obtained in decay-corrected maximal radiochemical yield of 37 % with a specific activity of 80 – 400 GBq/μmol. Treatment with rat and human microsomal enzymes in vitro for 60 min resulted in 20 % and 4 % of hydrophilic radiometabolites, respectively. No hydrophilic decomposition products or radiometabolites were found in PBS or plasma. In vitro autoradiography on rat brain slices showed a heterogeneous distribution consistent with the known distribution of mGlu5 with high binding to hippocampal and cortical regions, and negligible radioactivity in the cerebellum. Similar distribution of radioactivity was found in PET images. Under displacement conditions with 6, reduced [18F]5 binding was found in all brain regions except the cerebellum. 7 reduced binding in the striatum by 84 % on average. Test–retest studies were reproducible with a variability ranging from 6.8 % to 8.2 %. An extended single-dose toxicity study in Wistar rats showed no compound-related adverse effects. Conclusion The new mGlu5 radiotracer, [18F]5, showed specific and selective in vitro and in vivo properties and is a promising radioligand for PET imaging of mGlu5 in humans.
  • Preclinical development of [¹⁸F]TAAR1-2203 as a PET radioligand for imaging TAAR1 expression and receptor occupancy
    Item type: Journal Article
    Haider, Achi; Xiao, Zhiwei; Chen, Jiahui; et al. (2025)
    European Journal of Nuclear Medicine and Molecular Imaging
    Purpose Trace amine-associated receptor 1 (TAAR1) is an emerging therapeutic target with various implications in neuropsychiatric and metabolic disorders. However, the absence of a suitable positron emission tomography (PET) radioligand has precluded non-invasive quantification of TAAR1 expression and drug-receptor interactions in vivo. In this study, we report the preclinical development of [¹⁸F]TAAR1-2203, a fluorine-18 labeled PET ligand suitable to image TAAR1 expression in peripheral tissues. Methods [¹⁸F]TAAR1-2203 ([¹⁸F]RO5263397) was obtained via copper-mediated radiofluorination. In vitro stability was assessed in formulation, serum and using liver microsomes. Specific binding was evaluated by in vitro autoradiography, ex vivo biodistribution, and PET imaging under baseline and blockade conditions with structurally distinct TAAR1 agonists, as well as in TAAR1 knockout (KO) mice. Receptor occupancy studies were conducted in the pancreas - a peripheral organ with high physiological TAAR1 expression. Results TAAR1-2203 exhibited high TAAR1 affinity in competition binding assays across species, with Kᵢ values of 0.9 nM (mouse) and 5.7 nM (human). Tracer stability was corroborated by cross-species microsomal incubations and ex vivo radiometabolite analyses in mice. In peripheral tissues with known TAAR1 expression, [¹⁸F]TAAR1-2203 displayed robust signal intensity that was significantly reduced under pharmacological blockade or in TAAR1 KO mice, thus confirming specific receptor binding. Although [¹⁸F]TAAR1-2203 appeared to cross the blood-brain barrier based on brain time-activity curves and ex vivo radiometabolite analysis, no specific binding was observed in the CNS. Target occupancy studies in the pancreas demonstrated dose-dependent blockade, with a calculated D₅₀ of 0.67 mu mol/kg for a structurally distinct potent TAAR1 agonist. Conclusion [¹⁸F]TAAR1-2203 represents the first PET radioligand for TAAR1 imaging with favorable in vitro and in vivo performance characteristics, enabling non-invasive assessment of receptor expression and drug occupancy in peripheral TAAR1-expressing tissues. [¹⁸F]TAAR1-2203 holds promise for translational application in various drug development programs.
  • First-in-human administration of [¹⁶¹Tb]Tb-SibuDAB and comparative dosimetry with standard [¹⁷⁷Lu]Lu-PSMA-I&T as part of the PROGNOSTICS phase Ia study
    Item type: Other Journal Item
    Chirindel, Alin; Nicolas, Guillaume P.; Westerbergh, Frida; et al. (2025)
    European Journal of Nuclear Medicine and Molecular Imaging
  • Exploration of (R)-[11C]YH168 as a PET tracer for imaging monoacylglycerol lipase in the brain: from mice to non-human primates
    Item type: Journal Article
    He, Yingfang; Zheng, MingQiang; Gu, Jiwei; et al. (2025)
    European Journal of Nuclear Medicine and Molecular Imaging
    Purpose The monoacylglycerol lipase (MAGL) plays a pivotal role in modulating the endocannabinoid system and is considered an attractive therapeutic target for diseases in both the central nervous system and periphery. The current study aimed to develop and evaluate a suitable carbon-11 labeled tracer for imaging MAGL in preclinical studies. Methods (R)-YH168 was synthesized via a multi-step pathway and its half-maximal inhibitory concentration (IC50) values were measured using an enzymatic assay. Radiosynthesis of (R)-[11C]YH168 was accomplished by 11C-methylation via Suzuki cross-coupling of a pinacol boron precursor. In vitro autoradiography was performed using brain tissues from MAGL knockout and the corresponding wild-type mice. The metabolic stability of (R)-[11C]YH168 in mouse brain and plasma was assessed 5 min after injection. Dynamic PET scans were conducted on anesthetized mice and rhesus monkey. For studies in non-human primates, arterial blood samples were analyzed to obtain the input function for kinetic modeling. Blocking studies with the irreversible MAGL inhibitor PF-06795071 were performed to assess the binding specificity of (R)-[11C]YH168. Results (R)-[11C]YH168 was synthesized via Suzuki coupling of the phenyl boronic ester with [11C]CH3I in the presence of palladium catalyst. In vitro autoradiography revealed a heterogeneous distribution pattern of (R)-[11C]YH168 with higher binding to MAGL-rich brain regions in wild-type mouse brain slices compared to that of MAGL knockout mice. Dynamic PET imaging in wild-type and MAGL knockout mice confirmed its high specificity and selectivity in mouse brains. In the rhesus monkey, (R)-[11C]YH168 displayed good brain permeability. High levels of radioactivity uptake were seen in the cingulate cortex, frontal cortex, cerebellum, occipital cortex, and hippocampus, consistent with MAGL expression. The one-tissue compartment model was appropriate for fitting the regional time-activity curves and provided reliable volume of distribution values across all brain regions. Pretreatment with PF-06795071 (0.1 mg/kg) resulted in almost complete blockade (> 95%) of radioactivity uptake, demonstrating binding specificity of (R)-[11C]YH168 to MAGL in the non-human primate brain. The regional non-displaceable binding potential follows the rank order of cingulate cortex ~ frontal cortex ~ insula > putamen > temporal cortex > caudate ~ occipital cortex ~ thalamus > nucleus accumbens ~ hippocampus ~ cerebellum ~ globus pallidus > substantia nigra > amygdala. Conclusion (R)-[11C]YH168 is a promising PET probe for imaging and quantifying MAGL in the brains of mice and non-human primates. This 11C-labeled tracer holds great potential for translation into human subjects and offers the possibility of performing multiple PET scans on the same subject within a single day.
  • Combination of terbium-161 with somatostatin receptor antagonists—a potential paradigm shift for the treatment of neuroendocrine neoplasms
    Item type: Journal Article
    Borgna, Francesca; Haller, Stephanie; Monné Rodríguez, Josep M.; et al. (2022)
    European Journal of Nuclear Medicine and Molecular Imaging
    Purpose The β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). Methods The capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides’ tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. Results In vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. Conclusion The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs.
  • Non-invasive imaging of tau-targeted probe uptake by whole brain multi-spectral optoacoustic tomography
    Item type: Journal Article
    Vagenknecht, Patrick; Luzgin, Artur; Ono, Maiko; et al. (2022)
    European Journal of Nuclear Medicine and Molecular Imaging
    Purpose Abnormal tau accumulation within the brain plays an important role in tauopathies such as Alzheimer’s disease and frontotemporal dementia. High-resolution imaging of tau deposits at the whole-brain scale in animal disease models is highly desired. Methods We approached this challenge by non-invasively imaging the brains of P301L mice of 4-repeat tau with concurrent volumetric multi-spectral optoacoustic tomography (vMSOT) at ~ 115 μm spatial resolution using the tau-targeted pyridinyl-butadienyl-benzothiazole derivative PBB5 (i.v.). In vitro probe characterization, concurrent vMSOT and epi-fluorescence imaging of in vivo PBB5 targeting (i.v.) was performed in P301L and wild-type mice, followed by ex vivo validation using AT-8 antibody for phosphorylated tau. Results PBB5 showed specific binding to recombinant K18 tau fibrils by fluorescence assay, to post-mortem Alzheimer’s disease brain tissue homogenate by competitive binding against [11C]PBB3 and to tau deposits (AT-8 positive) in post-mortem corticobasal degeneration and progressive supranuclear palsy brains. Dose-dependent optoacoustic and fluorescence signal intensities were observed in the mouse brains following i.v. administration of different concentrations of PBB5. In vivo vMSOT brain imaging of P301L mice showed higher retention of PBB5 in the tau-laden cortex and hippocampus compared to wild-type mice, as confirmed by ex vivo vMSOT, epi-fluorescence, multiphoton microscopy, and immunofluorescence staining. Conclusions We demonstrated non-invasive whole-brain imaging of tau in P301L mice with vMSOT system using PBB5 at a previously unachieved ~ 115 μm spatial resolution. This platform provides a new tool to study tau spreading and clearance in a tauopathy mouse model, foreseeable in monitoring tau targeting putative therapeutics.
Publications1 - 10 of 83