TY - JOUR A1 - Matsusaka, Yohji A1 - Chen, Xinyu A1 - Arias-Loza, Paula A1 - Werner, Rudolf A. A1 - Nose, Naoko A1 - Sasaki, Takanori A1 - Rowe, Steven P. A1 - Pomper, Martin G. A1 - Lapa, Constantin A1 - Higuchi, Takahiro T1 - In Vivo Functional Assessment of Sodium-Glucose Cotransporters (SGLTs) Using [\(^{18}\)F]Me4FDG PET in Rats JF - Molecular Imaging N2 - 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. KW - Sodium-Glucose Cotransporters (SGLTs) KW - diabetes KW - rats Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300708 VL - 2022 ER - TY - JOUR A1 - Kosmala, Aleksander A1 - Serfling, Sebastian E. A1 - Dreher, Niklas A1 - Lindner, Thomas A1 - Schirbel, Andreas A1 - Lapa, Constantin A1 - Higuchi, Takahiro A1 - Buck, Andreas K. A1 - Weich, Alexander A1 - Werner, Rudolf A. T1 - Associations between normal organs and tumor burden in patients imaged with fibroblast activation protein inhibitor-directed positron emission tomography JF - Cancers N2 - (1) Background: We aimed to quantitatively investigate [\(^{68}\)Ga]Ga-FAPI-04 uptake in normal organs and to assess a relationship with the extent of FAPI-avid tumor burden. (2) Methods: In this single-center retrospective analysis, thirty-four patients with solid cancers underwent a total of 40 [\(^{68}\)Ga]Ga-FAPI-04 PET/CT scans. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were established by placing volumes of interest (VOIs) in the heart, liver, spleen, pancreas, kidneys, and bone marrow. Total tumor burden was determined by manual segmentation of tumor lesions with increased uptake. For tumor burden, quantitative assessment included maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA = TV × SUV\(_{mean}\)). Associations between uptake in normal organs and tumor burden were investigated by applying Spearman's rank correlation coefficient. (3) Results: Median SUV\(_{mean}\) values were 2.15 in the pancreas (range, 1.05–9.91), 1.42 in the right (range, 0.57–3.06) and 1.41 in the left kidney (range, 0.73–2.97), 1.2 in the heart (range, 0.46–2.59), 0.86 in the spleen (range, 0.55–1.58), 0.65 in the liver (range, 0.31–2.11), and 0.57 in the bone marrow (range, 0.26–0.94). We observed a trend towards significance for uptake in the myocardium and tumor-derived SUV\(_{max}\) (ρ = 0.29, p = 0.07) and TV (ρ = −0.30, p = 0.06). No significant correlation was achieved for any of the other organs: SUV\(_{max}\) (ρ ≤ 0.1, p ≥ 0.42), TV (ρ ≤ 0.11, p ≥ 0.43), and FTA (ρ ≤ 0.14, p ≥ 0.38). In a sub-analysis exclusively investigating patients with high tumor burden, significant correlations of myocardial uptake with tumor SUV\(_{max}\) (ρ = 0.44; p = 0.03) and tumor-derived FTA with liver uptake (ρ = 0.47; p = 0.02) were recorded. (4) Conclusions: In this proof-of-concept study, quantification of [\(^{68}\)Ga]Ga-FAPI-04 PET showed no significant correlation between normal organs and tumor burden, except for a trend in the myocardium. Those preliminary findings may trigger future studies to determine possible implications for treatment with radioactive FAP-targeted drugs, as higher tumor load or uptake may not lead to decreased doses in the majority of normal organs. KW - PET KW - [\(^{68}\)Ga]Ga-FAPI KW - theranostics KW - radioligand therapy KW - fibroblast activation protein Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275154 SN - 2072-6694 VL - 14 IS - 11 ER - TY - JOUR A1 - Löhr, Mario A1 - Härtig, Wolfgang A1 - Schulze, Almut A1 - Kroiß, Matthias A1 - Sbiera, Silviu A1 - Lapa, Constantin A1 - Mages, Bianca A1 - Strobel, Sabrina A1 - Hundt, Jennifer Elisabeth A1 - Bohnert, Simone A1 - Kircher, Stefan A1 - Janaki-Raman, Sudha A1 - Monoranu, Camelia-Maria T1 - SOAT1: A suitable target for therapy in high-grade astrocytic glioma? JF - International Journal of Molecular Sciences N2 - Targeting molecular alterations as an effective treatment for isocitrate dehydrogenase-wildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and IDH-mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages. KW - SOAT1 KW - glioblastoma KW - astrocytoma KW - IDH1/2 KW - lipid droplets KW - mitotane KW - targeted therapy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284178 SN - 1422-0067 VL - 23 IS - 7 ER - TY - JOUR A1 - Chen, Xinyu A1 - Werner, Rudolf A. A1 - Koshino, Kazuhiro A1 - Nose, Naoko A1 - Mühlig, Saskia A1 - Rowe, Steven P. A1 - Pomper, Martin G. A1 - Lapa, Constantin A1 - Decker, Michael A1 - Higuchi, Takahiro T1 - Molecular Imaging-Derived Biomarker of Cardiac Nerve Integrity - Introducing High NET Affinity PET Probe \(^{18}\)F-AF78 JF - Theranostics N2 - 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. KW - norepinephrine transporter KW - T-shaped π-π stacking KW - nonhuman primates KW - radiotracer kinetics KW - cardiac innervation imaging KW - sympathetic nervous system Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300685 VL - 12 IS - 9 SP - 4446 EP - 4458 ER - TY - JOUR A1 - Werner, Rudolf A. A1 - Habacha, Bilêl A1 - Lütje, Susanne A1 - Bundschuh, Lena A1 - Higuchi, Takahiro A1 - Hartrampf, Philipp A1 - Serfling, Sebastian E. A1 - Derlin, Thorsten A1 - Lapa, Constantin A1 - Buck, Andreas K. A1 - Essler, Markus A1 - Pienta, Kenneth J. A1 - Eisenberger, Mario A. A1 - Markowski, Mark C. A1 - Shinehouse, Laura A1 - AbdAllah, Rehab A1 - Salavati, Ali A1 - Lodge, Martin A. A1 - Pomper, Martin G. A1 - Gorin, Michael A. A1 - Bundschuh, Ralph A. A1 - Rowe, Steven P. T1 - High SUVs Have More Robust Repeatability in Patients with Metastatic Prostate Cancer: Results from a Prospective Test-Retest Cohort Imaged with \(^{18}\)F-DCFPyL JF - Molecular Imaging N2 - No abstract available. KW - SUV Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300748 VL - 2022 ER - TY - JOUR A1 - Matsusaka, Yohji A1 - Werner, Rudolf A. A1 - Arias-Loza, Paula A1 - Nose, Naoko A1 - Sasaki, Takanori A1 - Chen, Xinyu A1 - Lapa, Constantin A1 - Higuchi, Takahiro T1 - Performance Evaluation of a Preclinical SPECT Scanner with a Collimator Designed for Medium-Sized Animals JF - Molecular Imaging N2 - 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. KW - SPECT Scanner KW - medium-sized animals KW - performance Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300713 VL - 2022 ER - TY - JOUR A1 - Serfling, Sebastian E. A1 - Lapa, Constantin A1 - Dreher, Niklas A1 - Hartrampf, Philipp E. A1 - Rowe, Steven P. A1 - Higuchi, Takahiro A1 - Schirbel, Andreas A1 - Weich, Alexander A1 - Hahner, Stefanie A1 - Fassnacht, Martin A1 - Buck, Andreas K. A1 - Werner, Rudolf A. T1 - Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT JF - Molecular Imaging and Biology N2 - Background CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs. Methods Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden. Results Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found. Conclusions In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged. KW - CXCR4 KW - C-X-C motif chemokine receptor 4 KW - PET KW - [68Ga]PentixaFor KW - [177Lu]/[90Y]PentixaTher KW - theranostics KW - endoradiotherapy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324622 VL - 24 IS - 4 ER - TY - JOUR A1 - Weich, Alexander A1 - Higuchi, Takahiro A1 - Bundschuh, Ralph A. A1 - Lapa, Constantin A1 - Serfling, Sebastian E. A1 - Rowe, Steven P. A1 - Pomper, Martin G. A1 - Herrmann, Ken A1 - Buck, Andreas K. A1 - Derlin, Thorsten A1 - Werner, Rudolf A. T1 - Training on reporting and data system (RADS) for somatostatin-receptor targeted molecular imaging can reduce the test anxiety of inexperienced readers JF - Molecular Imaging and Biology N2 - Purpose For somatostatin receptor (SSTR)-positron emission tomography/computed tomography (PET/CT), a standardized framework termed SSTR-reporting and data system (RADS) has been proposed. We aimed to elucidate the impact of a RADS-focused training on reader’s anxiety to report on SSTR-PET/CT, the motivational beliefs in learning such a system, whether it increases reader’s confidence, and its implementation in clinical routine. Procedures A 3-day training course focusing on SSTR-RADS was conducted. Self-report questionnaires were handed out prior to the course (Pre) and thereafter (Post). The impact of the training on the following categories was evaluated: (1) test anxiety to report on SSTR-PET/CT, (2) motivational beliefs, (3) increase in reader’s confidence, and (4) clinical implementation. To assess the effect size of the course, Cohen’s d was calculated (small, d = 0.20; large effect, d = 0.80). Results Of 22 participants, Pre and Post were returned by 21/22 (95.5%). In total, 14/21 (66.7%) were considered inexperienced (IR, < 1 year experience in reading SSTR-PET/CTs) and 7/21 (33.3%) as experienced readers (ER, > 1 year). Applying SSTR-RADS, a large decrease in anxiety to report on SSTR-PET/CT was noted for IR (d =  − 0.74, P = 0.02), but not for ER (d = 0.11, P = 0.78). For the other three categories motivational beliefs, reader’s confidence, and clinical implementation, agreement rates were already high prior to the training and persisted throughout the course (P ≥ 0.21). Conclusions A framework-focused reader training can reduce anxiety to report on SSTR-PET/CTs, in particular for inexperienced readers. This may allow for a more widespread adoption of this system, e.g., in multicenter trials for better intra- and interindividual comparison of scan results. KW - PET/CT KW - neuroendocrine tumor KW - PRRT KW - peptide receptor radionuclide therapy KW - reporting and data system KW - SSTR-RADS KW - RADS Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324645 VL - 24 IS - 4 ER -