16222
2018
eng
100
Supplement No 1
59
conferenceobject
1
2018-05-27
--
--
The Impact of Ageing on [\(^{11}\)C]meta-Hydroxyephedrine Uptake in the Rat Heart
No abstract available.
Journal of Nuclear Medicine
0161-5505
http://jnm.snmjournals.org/content/59/supplement_1/100.abstract
urn:nbn:de:bvb:20-opus-162228
Johns Hopkins School of Medicine
Journal of Nuclear Medicine May 1, 2018 vol. 59 no. supplement 1 100
701983
Deutsches Urheberrecht
Rudolf A. Werner
Xinyu Chen
Mitsuru Hirano
Naoko Nose
Constantin Lapa
Mehrbod S. Javadi
Takahiro Higuchi
deu
swd
Positronen-Emissions-Tomografie
eng
uncontrolled
moycardial sympathetic innervation
deu
uncontrolled
Positronen-Emissions-Tomografie
eng
uncontrolled
positron emission tomography
eng
uncontrolled
PET
eng
uncontrolled
11C-HED
eng
uncontrolled
hydroxyephedrine
eng
uncontrolled
ageing
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
OpenAIRE
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16222/Werner_Rudolf_11C-HED_JNM_Kongressbeitrag_accepted_version.pdf
30070
2022
eng
2022
article
1
--
--
--
In Vivo Functional Assessment of Sodium-Glucose Cotransporters (SGLTs) Using [\(^{18}\)F]Me4FDG PET in Rats
Background. Mediating glucose absorption in the small intestine and renal clearance, sodium glucose cotransporters (SGLTs) have emerged as an attractive therapeutic target in diabetic patients. A substantial fraction of patients, however, only achieve inadequate glycemic control. Thus, we aimed to assess the potential of the SGLT-targeting PET radiotracer alpha-methyl-4-deoxy-4-[\(^{18}\)F]fluoro-D-glucopyranoside ([\(^{18}\)F]Me4FDG) as a noninvasive intestinal and renal biomarker of SGLT-mediated glucose transport. Methods. We investigated healthy rats using a dedicated small animal PET system. Dynamic imaging was conducted after administration of the reference radiotracer 2-deoxy-2-[\(^{18}\)F]fluoro-D-glucose ([\(^{18}\)F]FDG), or the SGLT-targeting agent, [\(^{18}\)F]Me4FDG either directly into the digestive tract (for assessing intestinal absorption) or via the tail vein (for evaluating kidney excretion). To confirm the specificity of [18F]Me4FDG and responsiveness to treatment, a subset of animals was also pretreated with the SGLT inhibitor phlorizin. In this regard, an intraintestinal route of administration was used to assess tracer absorption in the digestive tract, while for renal assessment, phlorizin was injected intravenously (IV). Results. Serving as reference, intestinal administration of [\(^{18}\)F]FDG led to slow absorption with retention of % of administered radioactivity at 15 min. [\(^{18}\)F]Me4FDG, however, was rapidly absorbed into the blood and cleared from the intestine within 15 min, leading to markedly lower tracer retention of % (). Intraintestinal phlorizin led to marked increase of [\(^{18}\)F]Me4FDG uptake (15 min, %; vs. untreated controls), supporting the notion that this PET agent can measure adequate SGLT inhibition in the digestive tract. In the kidneys, radiotracer was also sensitive to SGLT inhibition. After IV injection, [\(^{18}\)F]Me4FDG reabsorption in the renal cortex was significantly suppressed by phlorizin when compared to untreated animals (%ID/g at 60 min, vs. untreated controls, ; ). Conclusion. As a noninvasive read-out of the concurrent SGLT expression in both the digestive tract and the renal cortex, [\(^{18}\)F]Me4FDG PET may serve as a surrogate marker for treatment response to SGLT inhibition. As such, [\(^{18}\)F]Me4FDG may enable improvement in glycemic control in diabetes by PET-based monitoring strategies.
Molecular Imaging
10.1155/2022/4635171
urn:nbn:de:bvb:20-opus-300708
@articleMatsusaka.2022, author = Matsusaka, Yohji and Chen, Xinyu and Arias-Loza, Paula and Werner, Rudolf A. and Nose, Naoko and Sasaki, Takanori and Rowe, Steven P. and Pomper, Martin G. and Lapa, Constantin and Higuchi, Takahiro, year = 2022, title = In Vivo Functional Assessment of Sodium-Glucose Cotransporters (SGLTs) Using 18FMe4FDG PET in Rats, pages = 4635171, volume = 2022, journal = Molecular imaging, doi = 10.1155/2022/4635171,
md5:d95edc215de887150d956e1ad1035fc1
2023-01-23T07:14:08+00:00
/tmp/phpIl8ujD
bibtex
63ce33c010fed2.40760513
Molecular Imaging 2022, Vol 2022, Article ID 4635171. DOI: 10.1155/2022/4635171
false
true
Yohji Matsusaka
Xinyu Chen
Paula Arias-Loza
Rudolf A. Werner
Naoko Nose
Takanori Sasaki
Steven P. Rowe
Martin G. Pomper
Constantin Lapa
Takahiro Higuchi
eng
uncontrolled
Sodium-Glucose Cotransporters (SGLTs)
eng
uncontrolled
diabetes
eng
uncontrolled
rats
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Förderzeitraum 2022
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/30070/Molecular_Imaging_Matsusaka.pdf
16482
2018
eng
11120
8
article
1
2018-07-19
--
--
The Impact of Ageing on 11C-Hydroxyephedrine Uptake in the Rat Heart
We aimed to explore the impact of ageing on 11C-Hydroxyephedrine (11C-HED) uptake in the healthy rat heart in a longitudinal setting. To investigate a potential cold mass effect, the influence of specific activity on cardiac 11C-HED uptake was evaluated: 11C-HED was synthesized by N-methylation of (−)-metaraminol as the free base (radiochemical purity >95%) and a wide range of specific activities (0.2–141.9 GBq/μmol) were prepared. \(^{11}\)C-HED (48.7±9.7MBq, ranged 0.2–60.4μg/kg cold mass) was injected in healthy Wistar Rats. Dynamic 23-frame PET images were obtained over 30 min. Time activity curves were generated for the blood input function and myocardial tissue. Cardiac 11C-HED retention index (%/min) was calculated as myocardial tissue activity at 20-30 min divided by the integral of the blood activity curves. Additionally, the impact of ageing on myocardial 11CHED uptake was investigated longitudinally by PET studies at different ages of healthy Wistar Rats. A dose-dependent reduction of cardiac 11C-HED uptake was observed: The estimated retention index as a marker of norepinephrine function decreased at a lower specific activity (higher amount of cold mass). This observed high affinity of 11C-HED to the neural norepinephrine transporter triggered a subsequent study: In a longitudinal setting, the 11C-HED retention index decreased with increasing age. An age-related decline of cardiac sympathetic innervation could be demonstrated. The herein observed cold mass effect might increase in succeeding scans and therefore, 11C-HED microPET studies should be planned with extreme caution if one single radiosynthesis is scheduled for multiple animals.
Scientific Reports
10.1038/s41598-018-29509-0
2281-5872
urn:nbn:de:bvb:20-opus-164826
Johns Hopkins School of Medicine
Scientific Reports (2018) 8:11120. DOI:10.1038/s41598-018-29509-0
701983
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Rudolf A. Werner
Xinyu Chen
Yoshifumi Maya
Christoph Eissler
Mitsuru Hirano
Naoko Nose
Hiroshi Wakabayashi
Constantin Lapa
Mehrbod S. Javadi
Takahiro Higuchi
eng
uncontrolled
ageing
deu
swd
Positronen-Emissions-Tomografie
eng
uncontrolled
11C-HED
eng
uncontrolled
11C-Hydroxyephedrine
eng
uncontrolled
cardiac sympathetic nervous system
eng
uncontrolled
myocardial sympathetic innervation imaging
eng
uncontrolled
PET
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
OpenAIRE
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16482/Werner_Rudolf_Aging_11C-Hydroxyephedrine_SciRep_2018.pdf
26577
2021
eng
2021
article
1
2022-04-05
--
--
The number of frames on ECG-gated \(^{18}\)F-FDG small animal PET has a significant impact on LV systolic and diastolic functional parameters
Objectives. This study is aimed at investigating the impact of frame numbers in preclinical electrocardiogram- (ECG-) gated \(^{18}\)F-fluorodeoxyglucose (\(^{18}\)F-FDG) positron emission tomography (PET) on systolic and diastolic left ventricular (LV) parameters in rats. Methods. \(^{18}\)F-FDG PET imaging using a dedicated small animal PET system with list mode data acquisition and continuous ECG recording was performed in diabetic and control rats. The list-mode data was sorted and reconstructed with different numbers of frames (4, 8, 12, and 16) per cardiac cycle into tomographic images. Using an automatic ventricular edge detection software, left ventricular (LV) functional parameters, including ejection fraction (EF), end-diastolic (EDV), and end-systolic volume (ESV), were calculated. Diastolic variables (time to peak filling (TPF), first third mean filling rate (1/3 FR), and peak filling rate (PFR)) were also assessed. Results. Significant differences in multiple parameters were observed among the reconstructions with different frames per cardiac cycle. EDV significantly increased by numbers of frames (353.8 & PLUSMN; 57.7 mu l*, 380.8 & PLUSMN; 57.2 mu l*, 398.0 & PLUSMN; 63.1 mu l*, and 444.8 & PLUSMN; 75.3 mu l at 4, 8, 12, and 16 frames, respectively; *P < 0.0001 vs. 16 frames), while systolic (EF) and diastolic (TPF, 1/3 FR and PFR) parameters were not significantly different between 12 and 16 frames. In addition, significant differences between diabetic and control animals in 1/3 FR and PFR in 16 frames per cardiac cycle were observed (P < 0.005), but not for 4, 8, and 12 frames. Conclusions. Using ECG-gated PET in rats, measurements of cardiac function are significantly affected by the frames per cardiac cycle. Therefore, if you are going to compare those functional parameters, a consistent number of frames should be used.
Molecular Imaging
10.1155/2021/4629459
urn:nbn:de:bvb:20-opus-265778
publish
Molecular Imaging (2021) 2021:4629459. https://doi.org/10.1155/2021/4629459
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Cristoph Eissler
Rudolf A. Werner
Paula Arias-Loza
Naoko Nose
Xinyu Chen
Martin G. Pomper
Steven P. Rowe
Constantin Lapa
Andreas K. Buck
Takahiro Higuchi
eng
uncontrolled
Myocardial-perfusion SPECT
eng
uncontrolled
left-ventricular function
eng
uncontrolled
ejection fraction
eng
uncontrolled
MRI
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Deutsches Zentrum für Herzinsuffizienz (DZHI)
Förderzeitraum 2021
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/26577/4629459.pdf
16708
2018
eng
12
8
article
1
2018-08-10
--
--
Subcellular storage and release mode of the novel \(^{18}\)F-labeled sympathetic nerve PET tracer LMI1195
Background: \(^{18}\)F-N-[3-bromo-4-(3-fluoro-propoxy)-benzyl]-guanidine (\(^{18}\)F-LMI1195) is a new class of PET tracer designed for sympathetic nervous imaging of the heart. The favorable image quality with high and specific neural uptake has been previously demonstrated in animals and humans, but intracellular behavior is not yet fully understood. The aim of the present study is to verify whether it is taken up in storage vesicles and released in company with vesicle turnover.
Results: Both vesicle-rich (PC12) and vesicle-poor (SK-N-SH) norepinephrine-expressing cell lines were used for in vitro tracer uptake studies. After 2 h of \(^{18}\)F-LMI1195 preloading into both cell lines, effects of stimulants for storage vesicle turnover (high concentration KCl (100 mM) or reserpine treatment) were measured at 10, 20, and 30 min. \(^{131}\)I-meta-iodobenzylguanidine (\(^{131}\)I-MIBG) served as a reference. Both high concentration KCl and reserpine enhanced \(^{18}\)F-LMI1195 washout from PC12 cells, while tracer retention remained stable in the SK-N-SH cells. After 30 min of treatment, 18F-LMI1195 releasing index (percentage of tracer released from cells) from vesicle-rich PC12 cells achieved significant differences compared to cells without treatment condition. In contrast, such effect could not be observed using vesicle-poor SK-N-SH cell lines. Similar tracer kinetics after KCl or reserpine treatment were also observed using 131I-MIBG. In case of KCl exposure, Ca\(^{2+}\)-free buffer with the calcium chelator, ethylenediaminetetracetic acid (EDTA), could suppress the tracer washout from PC12 cells. This finding is consistent with the tracer release being mediated by Ca\(^{2+}\) influx resulting from membrane depolarization.
Conclusions: Analogous to \(^{131}\)I-MIBG, the current in vitro tracer uptake study confirmed that \(^{131}\)F-LMI1195 is also stored in vesicles in PC12 cells and released along with vesicle turnover. Understanding the basic kinetics of \(^{18}\)FLMI1195 at a subcellular level is important for the design of clinical imaging protocols and imaging interpretation.
EJNMMI Research
10.1186/s13550-018-0365-9
2191-219X
29411169
urn:nbn:de:bvb:20-opus-167081
Johns Hopkins School of Medicine
701983
EJNMMI Research (2018) 8:12 https://doi.org/10.1186/s13550-018-0365-9
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Xinyu Chen
Rudolf A. Werner
Constantin Lapa
Naoko Nose
Mitsuru Hirano
Mehrbod S. Javadi
Simon Robinson
Takahiro Higuchi
eng
uncontrolled
phaeochromocytoma
deu
swd
Positronen-Emissions-Tomografie
eng
uncontrolled
heart failure
eng
uncontrolled
sympathetic nervous system
eng
uncontrolled
storage vesicle turnover
eng
uncontrolled
positron emission tomography
eng
uncontrolled
18F-LMI1195
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
OpenAIRE
Förderzeitraum 2018
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/16708/Werner Rudolf LMI1195.pdf
26059
2021
eng
1
11
article
1
2022-03-16
--
--
[18F]FDG-labelled stem cell PET imaging in different route of administrations and multiple animal species
Stem cell therapy holds great promise for tissue regeneration and cancer treatment, although its efficacy is still inconclusive and requires further understanding and optimization of the procedures. Non-invasive cell tracking can provide an important opportunity to monitor in vivo cell distribution in living subjects. Here, using a combination of positron emission tomography (PET) and in vitro 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) direct cell labelling, the feasibility of engrafted stem cell monitoring was tested in multiple animal species. Human mesenchymal stem cells (MSCs) were incubated with phosphate-buffered saline containing [18F]FDG for in vitro cell radiolabelling. The pre-labelled MSCs were administrated via peripheral vein in a mouse (n=1), rats (n=4), rabbits (n=4) and non-human primates (n=3), via carotid artery in rats (n=4) and non-human primates (n=3), and via intra-myocardial injection in rats (n=5). PET imaging was started 10 min after cell administration using a dedicated small animal PET system for a mouse and rats. A clinical PET system was used for the imaging of rabbits and non-human primates. After MSC administration via peripheral vein, PET imaging revealed intense radiotracer signal from the lung in all tested animal species including mouse, rat, rabbit, and non-human primate, suggesting administrated MSCs were trapped in the lung tissue. Furthermore, the distribution of the PET signal significantly differed based on the route of cell administration. Administration via carotid artery showed the highest activity in the head, and intra-myocardial injection increased signal from the heart. In vitro [18F]FDG MSC pre-labelling for PET imaging is feasible and allows non-invasive visualization of initial cell distribution after different routes of cell administration in multiple animal models. Those results highlight the potential use of that imaging approach for the understanding and optimization of stem cell therapy in translational research.
Scientific Reports
10.1038/s41598-021-90383-4
urn:nbn:de:bvb:20-opus-260590
publish
Scientific Reports (2021) 11:1, 10896. https://doi.org/10.1038/s41598-021-90383-4
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Naoko Nose
Suguru Nogami
Kazuhiro Koshino
Xinyu Chen
Rudolf A. Werner
Soki Kashima
Steven P. Rowe
Constantin Lapa
Kazuki Fukuchi
Takahiro Higuchi
eng
uncontrolled
biomarkers
eng
uncontrolled
molecular medicine
eng
uncontrolled
stem-cell research
eng
uncontrolled
stem cells
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Deutsches Zentrum für Herzinsuffizienz (DZHI)
Förderzeitraum 2021
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/26059/s41598-021-90383-4.pdf
23061
2020
eng
10
article
1
2021-03-11
--
--
Capabilities of multi-pinhole SPECT with two stationary detectors for in vivo rat imaging
We aimed to investigate the image quality of the U-SPECT5/CT E-Class a micro single-photon emission computed tomography (SPECT) system with two large stationary detectors for visualization of rat hearts and bones using clinically available \(^{99m}\)Tc-labelled tracers. Sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR) of the small-animal SPECT scanner were investigated in phantom studies using an ultra-high-resolution rat and mouse multi-pinhole collimator (UHR-RM). Point source, hot-rod, and uniform phantoms with \(^{99m}\)Tc-solution were scanned for high-count performance assessment and count levels equal to animal scans, respectively. Reconstruction was performed using the similarity-regulated ordered-subsets expectation maximization (SROSEM) algorithm with Gaussian smoothing. Rats were injected with similar to 100 MBq [\(^{99m}\)TcTc-MIBI or similar to 150 MBq [\(^{99m}\)Tc]Tc-HMDP and received multi-frame micro-SPECT imaging after tracer distribution. Animal scans were reconstructed for three different acquisition times and post-processed with different sized Gaussian filters. Following reconstruction, CNR was calculated and image quality evaluated by three independent readers on a five-point scale from 1="very poor" to 5="very good". Point source sensitivity was 567 cps/MBq and radioactive rods as small as 1.2 mm were resolved with the UHR-RM collimator. Collimator-dependent uniformity was 55.5%. Phantom CNR improved with increasing rod size, filter size and activity concentration. Left ventricle and bone structures were successfully visualized in rat experiments. Image quality was strongly affected by the extent of post-filtering, whereas scan time did not have substantial influence on visual assessment. Good image quality was achieved for resolution range greater than 1.8 mm in bone and 2.8 mm in heart. The recently introduced small animal SPECT system with two stationary detectors and UHR-RM collimator is capable to provide excellent image quality in heart and bone scans in a rat using standardized reconstruction parameters and appropriate post-filtering. However, there are still challenges in achieving maximum system resolution in the sub-millimeter range with in vivo settings under limited injection dose and acquisition time.
Scientific Reports
10.1038/s41598-020-75696-0
urn:nbn:de:bvb:20-opus-230616
publish
Scientific Reports (2020) 10:18616. https://doi.org/10.1038/s41598-020-75696-0
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Jan P. Janssen
Jan V. Hoffmann
Takayuki Kanno
Naoko Nose
Jan-Peter Grunz
Masahisa Onoguchi
Xinyu Chen
Constantin Lapa
Andreas K. Buck
Takahiro Higuchi
eng
uncontrolled
small animal SPECT
eng
uncontrolled
HMDP hydroxymethylene diphosphonate
eng
uncontrolled
skeletal
eng
uncontrolled
quality
eng
uncontrolled
scanner
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Institut für diagnostische und interventionelle Radiologie (Institut für Röntgendiagnostik)
Deutsches Zentrum für Herzinsuffizienz (DZHI)
Förderzeitraum 2020
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/23061/41598_2020_Article_75696.pdf
30068
2022
eng
4446
4458
9
12
article
1
--
--
--
Molecular Imaging-Derived Biomarker of Cardiac Nerve Integrity - Introducing High NET Affinity PET Probe \(^{18}\)F-AF78
Background: Radiolabeled agents that are substrates for the norepinephrine transporter (NET) can be used to quantify cardiac sympathetic nervous conditions and have been demonstrated to identify high-risk congestive heart failure (HF) patients prone to arrhythmic events. We aimed to fully characterize the kinetic profile of the novel \(^{18}\)F-labeled NET probe AF78 for PET imaging of the cardiac sympathetic nervous system (SNS) among various species.
Methods: \(^{18}\)F-AF78 was compared to norepinephrine (NE) and established SNS radiotracers by employing in vitro cell assays, followed by an in vivo PET imaging approach with healthy rats, rabbits and nonhuman primates (NHPs). Additionally, chase protocols were performed in NHPs with NET inhibitor desipramine (DMI) and the NE releasing stimulator tyramine (TYR) to investigate retention kinetics in cardiac SNS.
Results: Relative to other SNS radiotracers, 18F-AF78 showed higher transport affinity via NET in a cell-based competitive uptake assay (IC\(^{50}\) 0.42 ± 0.14 µM), almost identical to that of NE (IC\(^{50}\), 0.50 ± 0.16 µM, n.s.). In rabbits and NHPs, initial cardiac uptake was significantly reduced by NET inhibition. Furthermore, cardiac tracer retention was not affected by a DMI chase protocol but was markedly reduced by intermittent TYR chase, thereby suggesting that \(^{18}\)F-AF78 is stored and can be released via the synaptic vesicular turnover process. Computational modeling hypothesized the formation of a T-shaped π-π stacking at the binding site, suggesting a rationale for the high affinity of \(^{18}\)F-AF78.
Conclusion: \(^{18}\)F-AF78 demonstrated high in vitro NET affinity and advantageous in vivo radiotracer kinetics across various species, indicating that \(^{18}\)F-AF78 is an SNS imaging agent with strong potential to guide specific interventions in cardiovascular medicine.
Theranostics
10.7150/thno.63205
urn:nbn:de:bvb:20-opus-300685
@articleChen.2022, author = Chen, Xinyu and Werner, Rudolf A. and Koshino, Kazuhiro and Nose, Naoko and Mühlig, Saskia and Rowe, Steven P. and Pomper, Martin G. and Lapa, Constantin and Decker, Michael and Higuchi, Takahiro, year = 2022, title = Molecular Imaging-Derived Biomarker of Cardiac Nerve Integrity - Introducing High NET Affinity PET Probe 18F-AF78, pages = 4446–4458, volume = 12, number = 9, journal = Theranostics, doi = 10.7150/thno.63205,
md5:fb4c26c82b049074d66c4ba92e23366f
2023-01-23T07:14:08+00:00
/tmp/phpIl8ujD
bibtex
63ce33c010fed2.40760513
Theranostics 2022, 12(9):4446-4458. DOI: 10.7150/thno.63205
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Xinyu Chen
Rudolf A. Werner
Kazuhiro Koshino
Naoko Nose
Saskia Mühlig
Steven P. Rowe
Martin G. Pomper
Constantin Lapa
Michael Decker
Takahiro Higuchi
eng
uncontrolled
norepinephrine transporter
eng
uncontrolled
T-shaped π-π stacking
eng
uncontrolled
nonhuman primates
eng
uncontrolled
radiotracer kinetics
eng
uncontrolled
cardiac innervation imaging
eng
uncontrolled
sympathetic nervous system
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Institut für Pharmazie und Lebensmittelchemie
Förderzeitraum 2022
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/30068/Theranostics_Chen.pdf
26987
2021
eng
505–515
4
23
article
1
--
--
--
Synthesis and Initial Characterization of a Reversible, Selective \(^{18}\)F-Labeled Radiotracer for Human Butyrylcholinesterase
Purpose
A neuropathological hallmark of Alzheimer's disease (AD) is the presence of amyloid-β (Aβ) plaques in the brain, which are observed in a significant number of cognitively normal, older adults as well. In AD, butyrylcholinesterase (BChE) becomes associated with A\(_{β}\) aggregates, making it a promising target for imaging probes to support diagnosis of AD. In this study, we present the synthesis, radiochemistry, in vitro and preliminary ex and in vivo investigations of a selective, reversible BChE inhibitor as PET-tracer for evaluation as an AD diagnostic.
Procedures
Radiolabeling of the inhibitor was achieved by fluorination of a respective tosylated precursor using K[\(^{18}\)F]. IC\(_{50}\) values of the fluorinated compound were obtained in a colorimetric assay using recombinant, human (h) BChE. Dissociation constants were determined by measuring hBChE activity in the presence of different concentrations of inhibitor.
Results
Radiofluorination of the tosylate precursor gave the desired radiotracer in an average radiochemical yield of 20 ± 3 %. Identity and > 95.5 % radiochemical purity were confirmed by HPLC and TLC autoradiography. The inhibitory potency determined in Ellman's assay gave an IC\(_{50}\) value of 118.3 ± 19.6 nM. Dissociation constants measured in kinetic experiments revealed lower affinity of the inhibitor for binding to the acylated enzyme (K2 = 68.0 nM) in comparison to the free enzyme (K\(_{1}\) = 32.9 nM).
Conclusions
The reversibly acting, selective radiotracer is synthetically easily accessible and retains promising activity and binding potential on hBChE. Radiosynthesis with \(^{18}\)F labeling of tosylates was feasible in a reasonable time frame and good radiochemical yield.
Molecular Imaging and Biology
1860-2002
10.1007/s11307-021-01584-2
33660167
urn:nbn:de:bvb:20-opus-269870
publish
Molecular Imaging and Biology 2021, 23(4):505–515. DOI: 10.1007/s11307-021-01584-2
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Christian Gentzsch
Xinyu Chen
Philipp Spatz
Urban Košak
Damijan Knez
Naoko Nose
Stanislav Gobec
Takahiro Higuchi
Michael Decker
eng
uncontrolled
Alzheimer’s disease
eng
uncontrolled
amyloid-β (Aβ)
eng
uncontrolled
butyrylcholinesterase
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Institut für Pharmazie und Lebensmittelchemie
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/26987/Gentzsch_Molecular.pdf
23990
2021
eng
1427
1437
9
16
article
1
--
--
--
Synthesis and Initial Characterization of a Selective, Pseudo‐irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer
The enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer's disease (AD) and to monitor disease progression in some forms of cancer. In this study, we present the design, facile synthesis, in vitro and preliminary ex vivo and in vivo evaluation of a morpholine‐based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo‐irreversible binding mode. We demonstrate a novel protecting group strategy for 18F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound. In particular, the prolonged duration of enzyme inhibition of such a morpholinocarbamate motivated us to design a PET tracer, possibly enabling a precise mapping of BChE distribution.
ChemMedChem
10.1002/cmdc.202000942
urn:nbn:de:bvb:20-opus-239904
2021-06-14T16:52:31+00:00
sword
swordwue
attachment; filename=deposit.zip
45f3f5c2560eb478c6d9a619d5584c3b
ChemMedChem 2021, 16(9):1427-1437. DOI: 10.1002/cmdc.202000942
false
true
CC BY-NC-ND: Creative-Commons-Lizenz: Namensnennung, Nicht kommerziell, Keine Bearbeitungen 4.0 International
Christian Gentzsch
Matthias Hoffmann
Yasuhiro Ohshima
Naoko Nose
Xinyu Chen
Takahiro Higuchi
Michael Decker
eng
uncontrolled
carbamate
eng
uncontrolled
enzyme kinetics
eng
uncontrolled
fluorine-18
eng
uncontrolled
positron emission tomography
eng
uncontrolled
radiotracers
Chemie und zugeordnete Wissenschaften
open_access
Klinik und Poliklinik für Nuklearmedizin
Institut für Pharmazie und Lebensmittelchemie
Import
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/23990/CMDC_CMDC202000942.pdf
30071
2022
eng
2022
article
1
--
--
--
Performance Evaluation of a Preclinical SPECT Scanner with a Collimator Designed for Medium-Sized Animals
Background. Equipped with two stationary detectors, a large bore collimator for medium-sized animals has been recently introduced for dedicated preclinical single-photon emission computed tomography (SPECT) imaging. We aimed to evaluate the basic performance of the system using phantoms and healthy rabbits. Methods. A general-purpose medium-sized animal (GP-MSA) collimator with 135 mm bore diameter and thirty-three holes of 2.5 mm diameter was installed on an ultrahigh-resolution scanner equipped with two large stationary detectors (U-SPECT5-E/CT). The sensitivity and uniformity were investigated using a point source and a cylinder phantom containing 99mTc-pertechnetate, respectively. Uniformity (in %) was derived using volumes of interest (VOIs) on images of the cylinder phantom and calculated as , with lower values of % indicating superior performance. The spatial resolution and contrast-to-noise ratios (CNRs) were evaluated with images of a hot-rod Derenzo phantom using different activity concentrations. Feasibility of in vivo SPECT imaging was finally confirmed by rabbit imaging with the most commonly used clinical myocardial perfusion SPECT agent [99mTc]Tc-sestamibi (dynamic acquisition with a scan time of 5 min). Results. In the performance evaluation, a sensitivity of 790 cps/MBq, a spatial resolution with the hot-rod phantom of 2.5 mm, and a uniformity of 39.2% were achieved. The CNRs of the rod size 2.5 mm were 1.37, 1.24, 1.20, and 0.85 for activity concentration of 29.2, 1.0, 0.5, and 0.1 MBq/mL, respectively. Dynamic SPECT imaging in rabbits allowed to visualize most of the thorax and to generate time-activity curves of the left myocardial wall and ventricular cavity. Conclusion. Preclinical U-SPECT5-E/CT equipped with a large bore collimator demonstrated adequate sensitivity and resolution for in vivo rabbit imaging. Along with its unique features of SPECT molecular functional imaging is a superior collimator technology that is applicable to medium-sized animal models and thus may promote translational research for diagnostic purposes and development of novel therapeutics.
Molecular Imaging
10.1155/2022/9810097
urn:nbn:de:bvb:20-opus-300713
@articleMatsusaka.2022b, author = Matsusaka, Yohji and Werner, Rudolf A. and Arias-Loza, Paula and Nose, Naoko and Sasaki, Takanori and Chen, Xinyu and Lapa, Constantin and Higuchi, Takahiro, year = 2022, title = Performance Evaluation of a Preclinical SPECT Scanner with a Collimator Designed for Medium-Sized Animals, pages = 9810097, volume = 2022, journal = Molecular imaging, doi = 10.1155/2022/9810097,
md5:72cac27ac231904f547cec93ce22a1d8
2023-01-23T07:14:08+00:00
/tmp/phpIl8ujD
bibtex
63ce33c010fed2.40760513
Molecular Imaging 2022, Vol 2022, Article ID 9810097. DOI: 10.1155/2022/9810097
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Yohji Matsusaka
Rudolf A. Werner
Paula Arias-Loza
Naoko Nose
Takanori Sasaki
Xinyu Chen
Constantin Lapa
Takahiro Higuchi
eng
uncontrolled
SPECT Scanner
eng
uncontrolled
medium-sized animals
eng
uncontrolled
performance
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Förderzeitraum 2022
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/30071/Molecular_Matsuaka.pdf
30394
2023
eng
2
15
article
1
--
2023-02-17
--
Rationalizing the binding modes of PET radiotracers targeting the norepinephrine transporter
Purpose: A new PET radiotracer \(^{18}\)F-AF78 showing great potential for clinical application has been reported recently. It belongs to a new generation of phenethylguanidine-based norepinephrine transporter (NET)-targeting radiotracers. Although many efforts have been made to develop NET inhibitors as antidepressants, systemic investigations of the structure–activity relationships (SARs) of NET-targeting radiotracers have rarely been performed. Methods: Without changing the phenethylguanidine pharmacophore and 3-fluoropropyl moiety that is crucial for easy labeling, six new analogs of \(^{18}\)F-AF78 with different meta-substituents on the benzene-ring were synthesized and evaluated in a competitive cellular uptake assay and in in vivo animal experiments in rats. Computational modeling of these tracers was established to quantitatively rationalize the interaction between the radiotracers and NET. Results: Using non-radiolabeled reference compounds, a competitive cellular uptake assay showed a decrease in NET-transporting affinity from meta-fluorine to iodine (0.42 and 6.51 µM, respectively), with meta-OH being the least active (22.67 µM). Furthermore, in vivo animal studies with radioisotopes showed that heart-to-blood ratios agreed with the cellular experiments, with AF78(F) exhibiting the highest cardiac uptake. This result correlates positively with the electronegativity rather than the atomic radius of the meta-substituent. Computational modeling studies revealed a crucial influence of halogen substituents on the radiotracer–NET interaction, whereby a T-shaped π–π stacking interaction between the benzene-ring of the tracer and the amino acid residues surrounding the NET binding site made major contributions to the different affinities, in accordance with the pharmacological data. Conclusion: The SARs were characterized by in vitro and in vivo evaluation, and computational modeling quantitatively rationalized the interaction between radiotracers and the NET binding site. These findings pave the way for further evaluation in different species and underline the potential of AF78(F) for clinical application, e.g., cardiac innervation imaging or molecular imaging of neuroendocrine tumors.
Pharmaceutics
1999-4923
10.3390/pharmaceutics15020690
urn:nbn:de:bvb:20-opus-303949
2023-03-14T05:52:25+00:00
sword
swordwue
attachment; filename=deposit.zip
0163457f22e9ed16b9172737a681a8f1
Pharmaceutics (2023) 15:2, 690. https://doi.org/10.3390/pharmaceutics15020690
false
true
CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International
Anna Tutov
Xinyu Chen
Rudolf A. Werner
Saskia Mühlig
Thomas Zimmermann
Naoko Nose
Kazuhiro Koshino
Constantin Lapa
Michael Decker
Takahiro Higuchi
eng
uncontrolled
positron emission tomography
eng
uncontrolled
norepinephrine transporter
eng
uncontrolled
sympathetic nervous system
eng
uncontrolled
structure–activity relationships
eng
uncontrolled
T-shaped π–π stacking
Medizin und Gesundheit
open_access
Klinik und Poliklinik für Nuklearmedizin
Institut für Pharmazie und Lebensmittelchemie
Import
Deutsches Zentrum für Herzinsuffizienz (DZHI)
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/30394/pharmaceutics-15-00690.pdf