@inproceedings{WernerChenHiranoetal.2018,
  author    = {Werner, Rudolf A. and Chen, Xinyu and Hirano, Mitsuru and Nose, Naoko and Lapa, Constantin and Javadi, Mehrbod S. and Higuchi, Takahiro},
  title     = {The Impact of Ageing on [\(^{11}\)C]meta-Hydroxyephedrine Uptake in the Rat Heart},
  series = {Journal of Nuclear Medicine},
  volume    = {59},
  booktitle = {Journal of Nuclear Medicine},
  number    = {Supplement No 1},
  issn      = {0161-5505},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-162228},
  pages     = {100},
  year      = {2018},
  abstract  = {No abstract available.},
  subject      = {Positronen-Emissions-Tomografie},
  language  = {en}
}
@article{GentzschHoffmannOhshimaetal.2021,
  author    = {Gentzsch, Christian and Hoffmann, Matthias and Ohshima, Yasuhiro and Nose, Naoko and Chen, Xinyu and Higuchi, Takahiro and Decker, Michael},
  title     = {Synthesis and Initial Characterization of a Selective, Pseudo-irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer},
  series = {ChemMedChem},
  volume    = {16},
  journal   = {ChemMedChem},
  number    = {9},
  doi       = {10.1002/cmdc.202000942},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239904},
  pages     = {1427 -- 1437},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{ChenWernerLapaetal.2018,
  author    = {Chen, Xinyu and Werner, Rudolf A. and Lapa, Constantin and Nose, Naoko and Hirano, Mitsuru and Javadi, Mehrbod S. and Robinson, Simon and Higuchi, Takahiro},
  title     = {Subcellular storage and release mode of the novel \(^{18}\)F-labeled sympathetic nerve PET tracer LMI1195},
  series = {EJNMMI Research},
  volume    = {8},
  journal   = {EJNMMI Research},
  number    = {12},
  issn      = {2191-219X},
  doi       = {10.1186/s13550-018-0365-9},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167081},
  year      = {2018},
  abstract  = {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.},
  subject      = {Positronen-Emissions-Tomografie},
  language  = {en}
}
@article{TutovChenWerneretal.2023,
  author    = {Tutov, Anna and Chen, Xinyu and Werner, Rudolf A. and M{\"u}hlig, Saskia and Zimmermann, Thomas and Nose, Naoko and Koshino, Kazuhiro and Lapa, Constantin and Decker, Michael and Higuchi, Takahiro},
  title     = {Rationalizing the binding modes of PET radiotracers targeting the norepinephrine transporter},
  series = {Pharmaceutics},
  volume    = {15},
  journal   = {Pharmaceutics},
  number    = {2},
  issn      = {1999-4923},
  doi       = {10.3390/pharmaceutics15020690},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303949},
  year      = {2023},
  abstract  = {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.},
  language  = {en}
}