{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:51:13Z","timestamp":1790855473663,"version":"4.1.0"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,17]],"date-time":"2023-02-17T00:00:00Z","timestamp":1676592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft","award":["453989101"],"award-info":[{"award-number":["453989101"]}]},{"name":"Deutsche Forschungsgemeinschaft","award":["507803309"],"award-info":[{"award-number":["507803309"]}]},{"name":"Deutsche Forschungsgemeinschaft","award":["22H03027"],"award-info":[{"award-number":["22H03027"]}]},{"name":"Deutsche Forschungsgemeinschaft","award":["K-BM-2013-247"],"award-info":[{"award-number":["K-BM-2013-247"]}]},{"name":"Deutsche Forschungsgemeinschaft","award":["GRK2243"],"award-info":[{"award-number":["GRK2243"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["453989101"],"award-info":[{"award-number":["453989101"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["507803309"],"award-info":[{"award-number":["507803309"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["22H03027"],"award-info":[{"award-number":["22H03027"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["K-BM-2013-247"],"award-info":[{"award-number":["K-BM-2013-247"]}]},{"name":"Japan Society for the Promotion of Science (JSPS)","award":["GRK2243"],"award-info":[{"award-number":["GRK2243"]}]},{"name":"International Doctoral Program \u201cReceptor Dynamics: Emerging Paradigms for Novel Drugs\u201d within the framework of the Elite Network of Bavaria","award":["453989101"],"award-info":[{"award-number":["453989101"]}]},{"name":"International Doctoral Program \u201cReceptor Dynamics: Emerging Paradigms for Novel Drugs\u201d within the framework of the Elite Network of Bavaria","award":["507803309"],"award-info":[{"award-number":["507803309"]}]},{"name":"International Doctoral Program \u201cReceptor Dynamics: Emerging Paradigms for Novel Drugs\u201d within the framework of the Elite Network of Bavaria","award":["22H03027"],"award-info":[{"award-number":["22H03027"]}]},{"name":"International Doctoral Program \u201cReceptor Dynamics: Emerging Paradigms for Novel Drugs\u201d within the framework of the Elite Network of Bavaria","award":["K-BM-2013-247"],"award-info":[{"award-number":["K-BM-2013-247"]}]},{"name":"International Doctoral Program \u201cReceptor Dynamics: Emerging Paradigms for Novel Drugs\u201d within the framework of the Elite Network of Bavaria","award":["GRK2243"],"award-info":[{"award-number":["GRK2243"]}]},{"name":"Doctoral Program \u201cUnderstanding Ubiquitylation: From Molecular Mechanisms to Disease\u201d","award":["453989101"],"award-info":[{"award-number":["453989101"]}]},{"name":"Doctoral Program \u201cUnderstanding Ubiquitylation: From Molecular Mechanisms to Disease\u201d","award":["507803309"],"award-info":[{"award-number":["507803309"]}]},{"name":"Doctoral Program \u201cUnderstanding Ubiquitylation: From Molecular Mechanisms to Disease\u201d","award":["22H03027"],"award-info":[{"award-number":["22H03027"]}]},{"name":"Doctoral Program \u201cUnderstanding Ubiquitylation: From Molecular Mechanisms to Disease\u201d","award":["K-BM-2013-247"],"award-info":[{"award-number":["K-BM-2013-247"]}]},{"name":"Doctoral Program \u201cUnderstanding Ubiquitylation: From Molecular Mechanisms to Disease\u201d","award":["GRK2243"],"award-info":[{"award-number":["GRK2243"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Purpose: A new PET radiotracer 18F-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\u2013activity 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 18F-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 \u00b5M, respectively), with meta-OH being the least active (22.67 \u00b5M). 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\u2013NET interaction, whereby a T-shaped \u03c0\u2013\u03c0 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.<\/jats:p>","DOI":"10.3390\/pharmaceutics15020690","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T05:27:01Z","timestamp":1676870821000},"page":"690","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Rationalizing the Binding Modes of PET Radiotracers Targeting the Norepinephrine Transporter"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2345-0648","authenticated-orcid":false,"given":"Anna","family":"Tutov","sequence":"first","affiliation":[{"name":"Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg, D-97074 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6165-1689","authenticated-orcid":false,"given":"Xinyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Nuclear Medicine, Faculty of Medicine, University of Augsburg, D-86156 Augsburg, Germany"},{"name":"Department of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital W\u00fcrzburg, D-97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolf A.","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital W\u00fcrzburg, D-97080 W\u00fcrzburg, Germany"},{"name":"Division of Nuclear Medicine, The Russell H Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia","family":"M\u00fchlig","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital W\u00fcrzburg, D-97080 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1417-4971","authenticated-orcid":false,"given":"Thomas","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg, D-97074 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoko","family":"Nose","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-0082, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3316-3968","authenticated-orcid":false,"given":"Kazuhiro","family":"Koshino","sequence":"additional","affiliation":[{"name":"Department of Systems and Informatics, Hokkaido Information University, Ebetsu 069-0832, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7536-2207","authenticated-orcid":false,"given":"Constantin","family":"Lapa","sequence":"additional","affiliation":[{"name":"Nuclear Medicine, Faculty of Medicine, University of Augsburg, D-86156 Augsburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6773-6245","authenticated-orcid":false,"given":"Michael","family":"Decker","sequence":"additional","affiliation":[{"name":"Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry, University of W\u00fcrzburg, D-97074 W\u00fcrzburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9711-7835","authenticated-orcid":false,"given":"Takahiro","family":"Higuchi","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine and Comprehensive Heart Failure Center, University Hospital W\u00fcrzburg, D-97080 W\u00fcrzburg, Germany"},{"name":"Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-0082, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1152\/physrev.1990.70.4.963","article-title":"Overflow of catecholamine neurotransmitters to the circulation: Source, fate, and functions","volume":"70","author":"Esler","year":"1990","journal-title":"Physiol. 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