Refine
Has Fulltext
- yes (69)
Is part of the Bibliography
- yes (69)
Year of publication
Document Type
- Journal article (60)
- Preprint (6)
- Conference Proceeding (3)
Language
- English (69)
Keywords
- PET (17)
- Positronen-Emissions-Tomografie (16)
- prostate cancer (13)
- theranostics (11)
- positron emission tomography (10)
- PSMA (7)
- neuroendocrine tumor (7)
- radioligand therapy (7)
- CXCR4 (6)
- PET/CT (6)
Institute
- Klinik und Poliklinik für Nuklearmedizin (69)
- Medizinische Klinik und Poliklinik II (10)
- Medizinische Klinik und Poliklinik I (9)
- Deutsches Zentrum für Herzinsuffizienz (DZHI) (8)
- Urologische Klinik und Poliklinik (8)
- Institut für Pharmazie und Lebensmittelchemie (4)
- Comprehensive Cancer Center Mainfranken (3)
- Pathologisches Institut (3)
- Institut für Anatomie und Zellbiologie (2)
- Institut für Klinische Biochemie und Pathobiochemie (2)
- Institut für diagnostische und interventionelle Radiologie (Institut für Röntgendiagnostik) (2)
- Center for Computational and Theoretical Biology (1)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (1)
- Klinik und Poliklinik für Anästhesiologie (ab 2004) (1)
- Klinik und Poliklinik für Dermatologie, Venerologie und Allergologie (1)
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (1)
Sonstige beteiligte Institutionen
- Johns Hopkins School of Medicine (15)
- Department of Biomedical Imaging, National Cerebral and Cardiovascular Research Center, Suita, Japan (2)
- Division of Medical Technology and Science, Department of Medical Physics and Engineering, Course of Health Science, Osaka University Graduate School of Medicine, Suita Japan (2)
- Institut for Molecular Biology and CMBI, Department of Genomics, Stem Cell Biology and Regenerative Medicine, Leopold-Franzens-University Innsbruck, Innsbruck, Austria (2)
- Johns Hopkins School of Medicine, The Russell H Morgan Department of Radiology and Radiological Science, Baltimore, MD, USA (2)
- Johns Hopkins University School of Medicine (2)
- Department of Nuclear Medicine, Kanazawa University (1)
- Johns Hopkins Medicine (1)
- Johns Hopkins School of Medicine, Baltimore, MD, USA (1)
- Johns Hopkins University, Baltimore, MD, U.S. (1)
EU-Project number / Contract (GA) number
- 701983 (28)
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.