TY - JOUR A1 - Lambertini, Alessandro A1 - Hartrampf, Philipp E. A1 - Higuchi, Takahiro A1 - Serfling, Sebastian E. A1 - Meybohm, Patrick A1 - Schirbel, Andreas A1 - Buck, Andreas K. A1 - Werner, Rudolf A. T1 - CXCR4-targeted molecular imaging after severe SARS-Cov-2 infection JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - No abstract available. KW - CXCR4-targeting KW - SARS-CoV-2 KW - COVID-19 KW - molecular imaging Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324619 VL - 50 IS - 1 ER - TY - JOUR A1 - Higuchi, Takahiro A1 - Serfling, Sebastian E. A1 - Rowe, Steven P. A1 - Werner, Rudolf A. T1 - Therapeutic effects of lipid lowering medications on myocardial blood flow, inflammation, and sympathetic nerve activity using nuclear techniques JF - Current Cardiology Reports N2 - Purpose of Review Statins are routinely applied in patients with coronary artery disease, as they allow significantly to reduce blood cholesterol levels. Although those drugs are endorsed by current guidelines and prescribed routinely, a substantial portion of patients are still statin-intolerant and image-piloted strategies may then be helpful to identify patients that need further intensified treatment, e.g., to initiate treatment with proprotein convertase subtilisin / kexin type 9 inhibitors (PCSK9i). In addition, it has also been advocated that statins exhibit nonlipid, cardio-protective effects including improved cardiac nerve integrity, blood flow, and anti-inflammatory effects in congestive heart failure (HF) patients. Recent Findings In subjects after myocardial infarction treated with statins, \(^{123}\)I-metaiodobenzylguanidine (MIBG) scintigraphy has already revealed enhanced cardiac nerve function relative to patients without statins. In addition, all of those aforementioned statin-targeted pathways in HF can be visualized and monitored using dedicated cardiac radiotracers, e.g., \(^{123}\)I-MIBG or \(^{18}\)F-AF78 (for cardiac nerve function), \(^{18}\)F-flurpiridaz (to determine coronary flow) or \(^{68}\)Ga-PentixaFor (to detect inflammation). Summary Statins exhibit various cardio-beneficial effects, including improvement of cardiac nerve function, blood flow, and reduction of inflammation, which can all be imaged using dedicated nuclear cardiac radiotracers. This may allow for in vivo monitoring of statin-induced cardioprotection beyond lipid profiling in HF patients. KW - sympathetic nervous system KW - cardiac nerve KW - MIBG KW - inflammation KW - blood flow KW - statin Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324599 VL - 24 IS - 12 ER - TY - JOUR A1 - Tutov, Anna A1 - Chen, Xinyu A1 - Werner, Rudolf A. A1 - Mühlig, Saskia A1 - Zimmermann, Thomas A1 - Nose, Naoko A1 - Koshino, Kazuhiro A1 - Lapa, Constantin A1 - Decker, Michael A1 - Higuchi, Takahiro T1 - Rationalizing the binding modes of PET radiotracers targeting the norepinephrine transporter JF - Pharmaceutics N2 - 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. KW - positron emission tomography KW - norepinephrine transporter KW - sympathetic nervous system KW - structure–activity relationships KW - T-shaped π–π stacking Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303949 SN - 1999-4923 VL - 15 IS - 2 ER - TY - JOUR A1 - Hartrampf, Philipp E. A1 - Weinzierl, Franz-Xaver A1 - Buck, Andreas K. A1 - Rowe, Steven P. A1 - Higuchi, Takahiro A1 - Seitz, Anna Katharina A1 - Kübler, Hubert A1 - Schirbel, Andreas A1 - Essler, Markus A1 - Bundschuh, Ralph A. A1 - Werner, Rudolf A. T1 - Matched-pair analysis of [\(^{177}\)Lu]Lu-PSMA I&T and [\(^{177}\)Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer JF - European Journal of Nuclear Medicine and Molecular Imaging N2 - Background Labelled with lutetium-177, the urea-based small molecules PSMA I&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT. Materials and methods A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [\(^{177}\)Lu]Lu-PSMA I&T, and a matched cohort of 55 patients treated with [\(^{177}\)Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared. Results Toxicity assessment revealed grade III anaemia in a single patient (1.8%) for [\(^{177}\)Lu]Lu-PSMA I&T and five (9.1%) for [\(^{177}\)Lu]Lu-PSMA-617. In addition, one (1.9%) grade III thrombopenia for [\(^{177}\)Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [\(^{177}\)Lu]Lu-PSMA I&T did not differ significantly when compared to patients treated with [\(^{177}\)Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89). Conclusion In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed. KW - PSMA I&T KW - PSMA-617 KW - prostate-specific membrane antigen KW - prostate cancer KW - radioligand therapy KW - matched pair Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324581 VL - 49 IS - 9 ER -