Publications by authors named "Markus Schwaiger"

519 Publications

Effective rational humanization of a PASylated anti-galectin-3 Fab for the sensitive PET imaging of thyroid cancer in vivo.

Sci Rep 2021 Apr 1;11(1):7358. Epub 2021 Apr 1.

Lehrstuhl für Biologische Chemie, Technische Universität München, 85354, Freising (Weihenstephan), Germany.

The lack of a non-invasive test for malignant thyroid nodules makes the diagnosis of thyroid cancer (TC) challenging. Human galectin-3 (hGal3) has emerged as a promising target for medical TC imaging and diagnosis because of its exclusive overexpression in malignant thyroid tissues. We previously developed a human-chimeric αhGal3 Fab fragment derived from the rat monoclonal antibody (mAb) M3/38 with optimized clearance characteristics using PASylation technology. Here, we describe the elucidation of the hGal3 epitope recognized by mAb M3/38, X-ray crystallographic analysis of its complex with the chimeric Fab and, based on the three-dimensional structure, the rational humanization of the Fab by CDR grafting. Four CDR-grafted versions were designed using structurally most closely related fully human immunoglobulin V/V regions of which one-employing the acceptor framework regions of the HIV-1 neutralizing human antibody m66-showed the highest antigen affinity. By introducing two additional back-mutations to the rodent donor sequence, an affinity toward hGal3 indistinguishable from the chimeric Fab was achieved (K = 0.34 ± 0.02 nM in SPR). The PASylated humanized Fab was site-specifically labelled with the fluorescent dye Cy7 and applied for the immuno-histochemical staining of human tissue sections representative for different TCs. The same protein was conjugated with the metal chelator Dfo, followed by radiolabelling with Zr(IV). The resulting protein tracer allowed the highly sensitive and specific PET/CT imaging of orthotopic tumors in mice, which was confirmed by quantitative analysis of radiotracer accumulation. Thus, the PASylated humanized αhGal3 Fab offers clinical potential for the diagnostic imaging of TC.
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http://dx.doi.org/10.1038/s41598-021-86641-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016950PMC
April 2021

Diverse metabolic response of cancer cells treated with a Bi-anti-EGFR-immunoconjugate.

Sci Rep 2021 Mar 18;11(1):6227. Epub 2021 Mar 18.

Department of Chemistry, Bavarian NMR Center-Structural Membrane Biochemistry, Technische Universität München, Garching, Germany.

Evaluation of treatment response is among the major challenges in modern oncology. We herein used a monoclonal antibody targeting the EGF receptor (EGFR) labelled with the alpha emitter Bi (Bi-anti-EGFR-MAb). EJ28Luc (bladder) and LN18 (glioma) cancer cells, both overexpressing EGFR, were incubated for 3 h with the radioimmunoconjugate. To assess the responses in the core carbon metabolism upon this treatment, these cancer cell lines were subsequently cultivated for 18 h in the presence of [U-C]glucose. C-enrichment and isotopologue profiles of key amino acids were monitored by gas chromatography-mass spectrometry (GC/MS), in order to monitor the impacts of the radionuclide-treatment upon glucose metabolism. In comparison to untreated controls, treatment of EJ28Luc cells with Bi-anti-EGFR-MAb resulted in a significantly decreased incorporation of C from [U-C]glucose into alanine, aspartate, glutamate, glycine, proline and serine. In sharp contrast, the same amino acids did not display less C-enrichments during treatment of the LN18 cells. The data indicate early treatment response of the bladder cancer cells, but not of the glioma cells though cell lines were killed following Bi-anti-EGFR-MAb treatment. The pilot study shows that the C-labelling approach is a valid tool to assess the responsiveness of cancer cells upon radionuclide-treatment in considerable metabolic detail.
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http://dx.doi.org/10.1038/s41598-021-84421-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973706PMC
March 2021

Automated synthesis of [F]Ga-rhPSMA-7/ -7.3: results, quality control and experience from more than 200 routine productions.

EJNMMI Radiopharm Chem 2021 Jan 23;6(1). Epub 2021 Jan 23.

Chair of Pharmaceutical Radiochemistry, Technical University of Munich, Walther-Meißner-Str. 3, 85748, Garching, Germany.

Introduction: The radiohybrid (rh) prostate-specific membrane antigen (PSMA)-targeted ligand [F]Ga-rhPSMA-7 has previously been clinically assessed and demonstrated promising results for PET-imaging of prostate cancer. The ligand is present as a mixture of four stereoisomers ([F]Ga-rhPSMA-7.1, - 7.2, - 7.3 and - 7.4) and after a preclinical isomer selection process, [F]Ga-rhPSMA-7.3 has entered formal clinical trials. Here we report on the establishment of a fully automated production process for large-scale production of [F]Ga-rhPSMA-7/ -7.3 under GMP conditions (EudraLex).

Methods: [F]Fluoride in highly enriched [O]HO was retained on a strong anion exchange cartridge, rinsed with anhydrous acetonitrile and subsequently eluted with a solution of [K ⊂ 2.2.2]OH in anhydrous acetonitrile into a reactor containing Ga-rhPSMA ligand and oxalic acid in DMSO. F-for-F isotopic exchange at the Silicon-Fluoride Acceptor (SiFA) was performed at room temperature, followed by dilution with buffer and cartridge-based purification. Optimum process parameters were determined on the laboratory scale and thereafter implemented into an automated synthesis. Data for radiochemical yield (RCY), purity and quality control were analyzed for 243 clinical productions (160 for [F]Ga-rhPSMA-7; 83 for [F]Ga-rhPSMA-7.3).

Results: The automated production of [F]Ga-rhPSMA-7 and the single isomer [F]Ga-rhPSMA-7.3 is completed in approx. 16 min with an average RCY of 49.2 ± 8.6% and an excellent reliability of 98.8%. Based on the different starting activities (range: 31-130 GBq, 89 ± 14 GBq) an average molar activity of 291 ± 62 GBq/μmol (range: 50-450 GBq/μmol) was reached for labeling of 150 nmol (231 μg) precursor. Radiochemical purity, as measured by radio-high performance liquid chromatography and radio-thin layer chromatography, was 99.9 ± 0.2% and 97.8 ± 1.0%, respectively.

Conclusion: This investigation demonstrates that F-for-F isotopic exchange is well suited for the fast, efficient and reliable automated routine production of F-labeled PSMA-targeted ligands. Due to its simplicity, speed and robustness the development of further SiFA-based radiopharmaceuticals is highly promising and can be of far-reaching importance for future theranostic concepts.
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http://dx.doi.org/10.1186/s41181-021-00120-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826325PMC
January 2021

Hyperpolarized C pyruvate magnetic resonance spectroscopy for in vivo metabolic phenotyping of rat HCC.

Sci Rep 2021 Jan 13;11(1):1191. Epub 2021 Jan 13.

School of Medicine, Institute of Diagnostic and Interventional Radiology, Technical University of Munich, 81675, Munich, Germany.

The in vivo assessment of tissue metabolism represents a novel strategy for the evaluation of oncologic disease. Hepatocellular carcinoma (HCC) is a high-prevalence, high-mortality tumor entity often discovered at a late stage. Recent evidence indicates that survival differences depend on metabolic alterations in tumor tissue, with particular focus on glucose metabolism and lactate production. Here, we present an in vivo imaging technique for metabolic tumor phenotyping in rat models of HCC. Endogenous HCC was induced in Wistar rats by oral diethyl-nitrosamine administration. Peak lactate-to-alanine signal ratios (L/A) were assessed with hyperpolarized magnetic resonance spectroscopic imaging (HPMRSI) after [1-C]pyruvate injection. Cell lines were derived from a subset of primary tumors, re-implanted in nude rats, and assessed in vivo with dynamic hyperpolarized magnetic resonance spectroscopy (HPMRS) after [1-C]pyruvate injection and kinetic modelling of pyruvate metabolism, taking into account systemic lactate production and recirculation. For ex vivo validation, enzyme activity and metabolite concentrations were spectroscopically quantified in cell and tumor tissue extracts. Mean peak L/A was higher in endogenous HCC compared to non-tumorous tissue. Dynamic HPMRS revealed higher pyruvate-to-lactate conversion rates (k) and lactate signal in subcutaneous tumors derived from high L/A tumor cells, consistent with ex vivo measurements of higher lactate dehydrogenase (LDH) levels in these cells. In conclusion, HPMRS and HPMRSI reveal distinct tumor phenotypes corresponding to differences in glycolytic metabolism in HCC tumor tissue.
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http://dx.doi.org/10.1038/s41598-020-80952-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806739PMC
January 2021

Imaging atherosclerotic plaques by targeting Galectin-3 and activated macrophages using (Zr)-DFO- Galectin3-F(ab') mAb.

Theranostics 2021 1;11(4):1864-1876. Epub 2021 Jan 1.

Department of Nuclear Medicine, Klinikum rechts der Isar der TUM, Munich, Germany.

The high expression of Galectin-3 (Gal3) in macrophages of atherosclerotic plaques suggests its participation in atherosclerosis pathogenesis, and raises the possibility to use it as a target to image disease severity . Here, we explored the feasibility of tracking atherosclerosis by targeting Gal3 expression in plaques of apolipoprotein E knockout (ApoE-KO) mice PET imaging. Targeting of Gal3 in M0-, M1- and M2 (M2a/M2c)-polarized macrophages was assessed using a Gal3-F(ab') mAb labeled with AlexaFluor®488 and Zr- desferrioxamine-thioureyl-phenyl-isothiocyanate (DFO). To visualize plaques , ApoE-KO mice were injected i.v. with Zr-DFO-Gal3-F(ab') mAb and imaged via PET/CT 48 h post injection. Whole length aortas harvested from euthanized mice were processed for Sudan-IV staining, autoradiography, and immunostaining for Gal3, CD68 and α-SMA expression. To confirm accumulation of the tracer in plaques, ApoE-KO mice were injected i.v. with Cy5.5-Gal3-F(ab') mAb, euthanized 48 h post injection, followed by cryosections of the body and acquisition of fluorescent images. To explore the clinical potential of this imaging modality, immunostaining for Gal3, CD68 and α-SMA expression were carried out in human plaques. Single cell RNA sequencing (scRNA-Seq) analyses were performed to measure LGALS3 (i.e. a synonym for Gal3) gene expression in each macrophage of several subtypes present in murine or human plaques. Preferential binding to M2 macrophages was observed with both AlexaFluor®488-Gal3-F(ab') and Zr-DFO-Gal3-F(ab') mAbs. Focal and specific Zr-DFO-Gal3-F(ab') mAb uptake was detected in plaques of ApoE-KO mice by PET/CT. Autoradiography and immunohistochemical analyses of aortas confirmed the expression of Gal3 within plaques mainly in macrophages. Moreover, a specific fluorescent signal was visualized within the lesions of vascular structures burdened by plaques in mice. Gal3 expression in human plaques showed similar Gal3 expression patterns when compared to their murine counterparts. Our data reveal that Zr-DFO-Gal3-F(ab') mAb PET/CT is a potentially novel tool to image atherosclerotic plaques at different stages of development, allowing knowledge-based tailored individual intervention in clinically significant disease.
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http://dx.doi.org/10.7150/thno.50247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778602PMC
January 2021

From Tl to Tc-Sestamibi.

Authors:
Markus Schwaiger

J Nucl Med 2020 12;61(Suppl 2):110S-111S

Technical University of Munich, Munich, Germany

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http://dx.doi.org/10.2967/jnumed.120.251439DOI Listing
December 2020

Multiparametric PET and MRI of myocardial damage after myocardial infarction: correlation of integrin αvβ3 expression and myocardial blood flow.

Eur J Nucl Med Mol Imaging 2020 Sep 24. Epub 2020 Sep 24.

Department of Nuclear Medicine, School of Medicine, Technical University of Munich, Munich, Germany.

Purpose: Increased angiogenesis after myocardial infarction is considered an important favorable prognostic parameter. The αvβ3 integrin is a key mediator of cell-cell and cell-matrix interactions and an important molecular target for imaging of neovasculature and repair processes after MI. Thus, imaging of αvβ3 expression might provide a novel biomarker for assessment of myocardial angiogenesis as a prognostic marker of left ventricular remodeling after MI. Currently, there is limited data available regarding the association of myocardial blood flow and αvβ3 integrin expression after myocardial infarction in humans.

Methods: Twelve patients were examined 31 ± 14 days after MI with PET/CT using [F]Galacto-RGD and [N]NH and with cardiac MRI including late enhancement on the same day. Normal myocardium (remote) and areas of infarction (lesion) were identified on the [F]Galacto-RGD PET/CT images by correlation with [N]NH PET and cardiac MRI. Lesion/liver-, lesion/blood-, and lesion/remote ratios were calculated. Blood flow and [F]Galacto-RGD uptake were quantified and correlated for each myocardial segment (AHA 17-segment model).

Results: In 5 patients, increased [F]Galacto-RGD uptake was notable within or adjacent to the infarction areas with a lesion/remote ratio of 46% (26-83%; lesion/blood 1.15 ± 0.06; lesion/liver 0.61 ± 0.18). [F]Galacto-RGD uptake correlated significantly with infarct size (R = 0.73; p = 0.016). Moreover, it correlated significantly with restricted blood flow for all myocardial segments (R = - 0.39; p < 0.0001) and even stronger in severely hypoperfused areas (R = - 0.75; p < 0.0001).

Conclusion: [F]Galacto-RGD PET/CT allows the visualization and quantification of myocardial αvβ3 expression as a key player in angiogenesis in a subset of patients after MI. αvβ3 expression was more pronounced in patients with larger infarcts and was generally more intense but not restricted to areas with more impaired blood flow, proving that tracer uptake was largely independent of unspecific perfusion effects. Based on these promising results, larger prospective studies are warranted to evaluate the potential of αvβ3 imaging for assessment of myocardial angiogenesis and prediction of ventricular remodeling.
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http://dx.doi.org/10.1007/s00259-020-05034-zDOI Listing
September 2020

First Experience Using F-Flubrobenguane PET Imaging in Patients with Suspected Pheochromocytoma or Paraganglioma.

J Nucl Med 2021 Apr 28;62(4):479-485. Epub 2020 Aug 28.

Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

Pheochromocytomas and paragangliomas are a rare tumor entity originating from adrenomedullary chromaffin cells in the adrenal medulla or in sympathetic, paravertebral ganglia outside the medulla. Small lesions are especially difficult to detect by conventional CT or MRI and even by SPECT with the currently available radiotracers (e.g., metaiodobenzylguanidine [MIBG]). The novel PET radiotracer F-flubrobenguane could change the diagnostic paradigm in suspected pheochromocytomas and paragangliomas because of its homology with MIBG and the general advantages of PET imaging. The aim of this retrospective analysis was to evaluate F-flubrobenguane in pheochromocytomas and paragangliomas and to investigate the biodistribution in patients. Twenty-three patients with suspected pheochromocytoma or paraganglioma underwent PET/CT or PET/MRI at 63 ± 24 min after injection of 256 ± 33 MBq of F-flubrobenguane. The SUV and SUV of organs were measured with spheric volumes of interest. Threshold-segmented volumes of interest were used to measure the SUV or SUV of the tumor lesions. One reader evaluated all cross-sectional imaging datasets (CT or MRI) separately, as well as the PET hybrid datasets, and reported the lesion number and size. The diagnostic certainty for a positive lesion was scored on a 3-point scale. F-flubrobenguane showed a reproducible, stable biodistribution, with the highest SUV and SUV being in the thyroid gland (30.3 ± 2.2 and 22.5 ± 1.6, respectively), pancreas (12.2 ± 0.8 and 9.5 ± 0.7, respectively), and tumor lesions (16.8 ± 1.7 and 10.1 ± 1.1, respectively) and the lowest SUV and SUV being in muscle (1.1 ± 0.06 and 0.7 ± 0.04, respectively) and the lung (2.5 ± 0.17 and 1.85 ± 0.13, respectively). In a subgroup analysis, a significantly higher average SUV was seen for both pheochromocytoma and paraganglioma than for healthy adrenal glands (11.9 ± 2.0 vs. 9.9 ± 1.5 vs. 3.7 ± 0.2, respectively). In total, 47 lesions were detected. The reader reported more and smaller lesions with higher certainty in PET hybrid imaging than in conventional imaging; however, statistical significance was not reached. Of the 23 (23/47, 49%) lesions smaller than 1 cm, 61% (14/23) were found on hybrid imaging only. Our preliminary data suggest F-flubrobenguane PET to be a new, effective staging tool for patients with suspected pheochromocytoma or paraganglioma. Major advantages are the fast acquisition and high spatial resolution of PET imaging and the intense uptake in tumor lesions, facilitating detection. Further studies are warranted to define the role of F-flubrobenguane PET, particularly in comparison to standard diagnostic procedures such as MRI or I-MIBG SPECT/CT.
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http://dx.doi.org/10.2967/jnumed.120.248021DOI Listing
April 2021

A new class of PentixaFor- and PentixaTher-based theranostic agents with enhanced CXCR4-targeting efficiency.

Theranostics 2020 9;10(18):8264-8280. Epub 2020 Jul 9.

Chair for Pharmaceutical Radiochemistry, Faculties of Chemistry and Medicine, Technische Universität München, Garching, Germany.

Non-invasive PET imaging of CXCR4 expression in cancer and inflammation as well as CXCR4-targeted radioligand therapy (RLT) have recently found their way into clinical research by the development of the theranostic agents [Ga]PentixaFor (cyclo(D-Tyr-D-[NMe]Orn(AMBS-[Ga]DOTA)-Arg-Nal-Gly) = [Ga]DOTA-AMBS-CPCR4) and [Lu/Y]PentixaTher (cyclo(D-3-iodo-Tyr-D-[NMe]Orn(AMBS-[Lu/Y]DOTA)-Arg-Nal-Gly) = [Lu/Y]DOTA-AMBS-CPCR4). Although convincing clinical results have already been obtained with both agents, this study was designed to further investigate the required structural elements for improved ligand-receptor interaction for both peptide cores (CPCR4 and CPCR4). To this aim, a series of DOTA-conjugated CPCR4- and CPCR4-based ligands with new linker structures, replacing the AMBA-linker in PentixaFor and PentixaTher, were synthesized and evaluated. The investigation of the novel compounds alongside with the reference peptides PentixaFor and PentixaTher encompassed the determination of hCXCR4 and mCXCR4 affinity (IC) of the respective Ga-, Lu-, Y- and Bi-complexes in Jurkat and Eμ-myc 1080 cells using [I]FC-131 and [I]CPCR4.3 as radioligands, respectively, as well as the evaluation of the internalization and externalization kinetics of selected Ga- and Lu-labeled compounds in hCXCR4-transfected Chem-1 cells. Comparative small animal PET imaging studies (1h p.i.) as well as biodistribution studies (1, 6 and 48h p.i.) were performed in Daudi (human B cell lymphoma) xenograft bearing CB17 SCID mice. Based on the affinity data and cellular uptake studies, [Ga/Lu]DOTA-r-a-ABA-CPCR4 and [Ga/Lu]DOTA-r-a-ABA-CPCR4 (with r-a-ABA = D-Arg-D-Ala-4-aminobenzoyl-) were selected for further evaluation. Both analogs show app. 10-fold enhanced hCXCR4 affinity compared to the respective references [Ga]PentixaFor and [Lu]PentixaTher, four times higher cellular uptake in hCXCR4 expressing cells and improved cellular retention. Unfortunately, the improved binding and uptake characteristics of [Ga]DOTA-r-a-ABA-CPCR4 and -CPCR4 could not be recapitulated in initial PET imaging studies; both compounds showed similar uptake in the Daudi xenografts as [Ga]PentixaFor, alongside with higher background accumulation, especially in the kidneys. However, the subsequent biodistribution studies performed for the corresponding Lu-labeled analogs revealed a clear superiority of [Lu]DOTA-r-a-ABA-CPCR4 and [Lu]DOTA-r-a-ABA-CPCR4 over [Lu]PentixaTher with respect to tumor uptake (18.3±3.7 and 17.2±2.0 %iD/g, respectively, at 1h p.i. vs 12.4±3.7%iD/g for [Lu]PentixaTher) as well as activity retention in tumor up to 48h. Especially for [Lu]DOTA-r-a-ABA-CPCR4 with its low background accumulation, tumor/organ ratios at 48h were 2- to 4-fold higher than those obtained for [Lu]PentixaTher (except for kidney). The in-depth evaluation of a series of novel CPCR4- and CPCR4 analogs with modified linker structure has yielded reliable structure-activity relationships. It was generally observed that a) AMBA-by-ABA-substitution leads to enhanced ligand internalization, b) the extension of the ABA-linker by two additional amino acids (DOTA-Xaa-Xaa-ABA-) provides sufficient linker length to minimize the interaction of the [M]DOTA-chelate with the receptor, and that c) introduction of a cationic side chain (Xaa) greatly enhances receptor affinity of the constructs, obliterating the necessity for Tyr-iodination of the pentapeptide core to maintain high receptor affinity (such as in [Lu]PentixaTher). As a result, [Lu]DOTA-r-a-ABA-CPCR4 has emerged from this study as a powerful second-generation therapeutic CXCR4 ligand with greatly improved targeting efficiency and tumor retention and will be further evaluated in preclinical and clinical CXCR4-targeted dosimetry and RLT studies.
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http://dx.doi.org/10.7150/thno.45537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381729PMC
July 2020

Characterizing the heterogeneous metabolic progression in idiopathic REM sleep behavior disorder.

Neuroimage Clin 2020 26;27:102294. Epub 2020 May 26.

Department of Nuclear Medicine, University of Bern, Switzerland; Dept. Informatics, Technische Universität München, Munich, Germany.

Objective: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a prodromal stage of synucleinopathies such as Parkinson's disease (PD). Positron emission tomography (PET) with F-FDG reveals metabolic perturbations, which are scored by spatial covariance analysis. However, the resultant pattern scores do not capture the spatially heterogeneous trajectories of metabolic changes between individual brain regions. Assuming metabolic progression occurs as a continuum from the healthy control (HC) condition to iRBD and then PD, we investigated spatial dynamics of progressively perturbed glucose metabolism in a cross-sectional study.

Methods: 19 iRBD patients, 38 PD patients and 19 HC subjects underwent F-FDG PET. The images were spatially normalized, scaled to the global mean uptake, and automatically parcellated. We contrasted regional metabolism by group, and allocated the inferred progression to one of several possible trajectories. We further investigated the correlations between F-FDG uptake and the disease duration in the iRBD and PD groups, respectively. We also explored relationships between F-FDG uptake and the Unified Parkinson's Disease Rating Scale motor (UPDRS III) scores in the PD group.

Results: PD patients exhibited more extensive relative hyper- and hypo-metabolism than iRBD patients. We identified three dynamic metabolic trajectories, cross-sectional hypo- or hypermetabolism, cross-sectionally unchanged hypo- or hypermetabolism, cross-sectionally late hypo- or hypermetabolism, appearing only in the contrast of PD with iRBD. No correlation was found between relative F-FDG metabolism and disease duration in the iRBD group. Regional hyper- and hypo-metabolism in the PD patients correlated with disease duration or clinical UPDRS III scores.

Conclusion: Cerebral metabolism changes heterogeneously in a continuum extending from HC to iRBD and PD groups in this preliminary study. The distinctive metabolic trajectories point towards a potential neuroimaging biomarker for conversion of iRBD to frank PD, which should be amenable to advanced pattern recognition analysis in future longitudinal studies.
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http://dx.doi.org/10.1016/j.nicl.2020.102294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322340PMC
March 2021

Hybrid PET/MR imaging for the prediction of left ventricular recovery after percutaneous revascularisation of coronary chronic total occlusions.

Eur J Nucl Med Mol Imaging 2020 12 30;47(13):3074-3083. Epub 2020 May 30.

Klinik und Poliklinik für Innere Medizin I, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany.

Purpose: To evaluate myocardial viability assessment with hybrid 2-deoxy-2-[F]fluoro-D-glucose positron emission tomography/magnetic resonance imaging ([F]FDG-PET/MR) in predicting left ventricular (LV) wall motion recovery after percutaneous revascularisation of coronary chronic total occlusion (CTO).

Methods And Results: Forty-nine patients with CTO and corresponding wall motion abnormality (WMA) underwent [F]FDG-PET/MR imaging for viability assessment prior to percutaneous revascularisation. After 3-6 months, 23 patients underwent follow-up MR to evaluate wall motion recovery. In total, 124 segments were assigned to the CTO territories, while 80 segments displayed impaired wall motion. Of these, 68% (54) were concordantly viable in PET and MR; conversely, only 2 segments (2%) were assessed non-viable by both modalities. However, 30% showed a discordant viability pattern, either PET non-viable/MR viable (3 segments, 4%) or PET viable/MR non-viable (21 segments, 26%), and the latter revealed a significant wall motion improvement at follow-up (p = 0.033). Combined imaging by [F]FDG-PET/MR showed a fair accuracy in predicting myocardial recovery after CTO revascularisation (PET/MR area under ROC curve (AUC) = 0.72, p = 0.002), which was superior to LGE-MR (AUC = 0.66) and [F]FDG-PET (AUC = 0.58) alone.

Conclusion: Hybrid PET/MR imaging prior to CTO revascularisation predicts more accurately the recovery of dysfunctional myocardium than PET or MR alone. Its complementary information may identify regions of viable myocardium with increased potential for functional recovery.
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http://dx.doi.org/10.1007/s00259-020-04877-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680332PMC
December 2020

Intensive Care Risk Estimation in COVID-19 Pneumonia Based on Clinical and Imaging Parameters: Experiences from the Munich Cohort.

J Clin Med 2020 May 18;9(5). Epub 2020 May 18.

Department of Diagnostic and Interventional Radiology, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675 Munich, Germany.

The evolving dynamics of coronavirus disease 2019 (COVID-19) and the increasing infection numbers require diagnostic tools to identify patients at high risk for a severe disease course. Here we evaluate clinical and imaging parameters for estimating the need of intensive care unit (ICU) treatment. We collected clinical, laboratory and imaging data from 65 patients with confirmed COVID-19 infection based on polymerase chain reaction (PCR) testing. Two radiologists evaluated the severity of findings in computed tomography (CT) images on a scale from 1 (no characteristic signs of COVID-19) to 5 (confluent ground glass opacities in over 50% of the lung parenchyma). The volume of affected lung was quantified using commercially available software. Machine learning modelling was performed to estimate the risk for ICU treatment. Patients with a severe course of COVID-19 had significantly increased interleukin (IL)-6, C-reactive protein (CRP), and leukocyte counts and significantly decreased lymphocyte counts. The radiological severity grading was significantly increased in ICU patients. Multivariate random forest modelling showed a mean ± standard deviation sensitivity, specificity and accuracy of 0.72 ± 0.1, 0.86 ± 0.16 and 0.80 ± 0.1 and a receiver operating characteristic-area under curve (ROC-AUC) of 0.79 ± 0.1. The need for ICU treatment is independently associated with affected lung volume, radiological severity score, CRP, and IL-6.
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http://dx.doi.org/10.3390/jcm9051514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291055PMC
May 2020

Direct comparison of activation maps during galvanic vestibular stimulation: A hybrid H2[15 O] PET-BOLD MRI activation study.

PLoS One 2020 15;15(5):e0233262. Epub 2020 May 15.

German Center for Vertigo and Balance Disorders (DSGZ), University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.

Previous unimodal PET and fMRI studies in humans revealed a reproducible vestibular brain activation pattern, but with variations in its weighting and expansiveness. Hybrid studies minimizing methodological variations at baseline conditions are rare and still lacking for task-based designs. Thus, we applied for the first time hybrid 3T PET-MRI scanning (Siemens mMR) in healthy volunteers using galvanic vestibular stimulation (GVS) in healthy volunteers in order to directly compare H215O-PET and BOLD MRI responses. List mode PET acquisition started with the injection of 750 MBq H215O simultaneously to MRI EPI sequences. Group-level statistical parametric maps were generated for GVS vs. rest contrasts of PET, MR-onset (event-related), and MR-block. All contrasts showed a similar bilateral vestibular activation pattern with remarkable proximity of activation foci. Both BOLD contrasts gave more bilateral wide-spread activation clusters than PET; no area showed contradictory signal responses. PET still confirmed the right-hemispheric lateralization of the vestibular system, whereas BOLD-onset revealed only a tendency. The reciprocal inhibitory visual-vestibular interaction concept was confirmed by PET signal decreases in primary and secondary visual cortices, and BOLD-block decreases in secondary visual areas. In conclusion, MRI activation maps contained a mixture of CBF measured using H215O-PET and additional non-CBF effects, and the activation-deactivation pattern of the BOLD-block appears to be more similar to the H215O-PET than the BOLD-onset.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233262PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228124PMC
August 2020

First In-Human Medical Imaging with a PASylated Zr-Labeled Anti-HER2 Fab-Fragment in a Patient with Metastatic Breast Cancer.

Nucl Med Mol Imaging 2020 Apr 20;54(2):114-119. Epub 2020 Apr 20.

5Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany.

Purpose: PASylation® offers the ability to systematically tune and optimize the pharmacokinetics of protein tracers for molecular imaging. Here we report the first clinical translation of a PASylated Fab fragment (Zr∙Df-HER2-Fab-PAS) for the molecular imaging of tumor-related HER2 expression.

Methods: A patient with HER2-positive metastatic breast cancer received 37 MBq of Zr∙Df-HER2-Fab-PAS at a total mass dose of 70 μg. PET/CT was carried out 6, 24, and 45 h after injection, followed by image analysis of biodistribution, normal organ uptake, and lesion targeting.

Results: Images show a biodistribution typical for protein tracers, characterized by a prominent blood pool 6 h p.i., which decreased over time. Lesions were detectable as early as 24 h p.i. Zr∙Df-HER2-Fab-PAS was tolerated well.

Conclusion: This study demonstrates that a PASylated Fab tracer shows appropriate blood clearance to allow sensitive visualization of small tumor lesions in a clinical setting.
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http://dx.doi.org/10.1007/s13139-020-00638-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198682PMC
April 2020

CXCR4-Targeted PET Imaging of Central Nervous System B-Cell Lymphoma.

J Nucl Med 2020 12 24;61(12):1765-1771. Epub 2020 Apr 24.

Internal Medicine III, School of Medicine, Technische Universität München, Munich, Germany

C-X-C chemokine receptor 4 (CXCR4) is a transmembrane chemokine receptor involved in growth, survival, and dissemination of cancer, including aggressive B-cell lymphoma. MRI is the standard imaging technology for central nervous system (CNS) involvement of B-cell lymphoma and provides high sensitivity but moderate specificity. Therefore, novel molecular and functional imaging strategies are urgently required. In this proof-of-concept study, 11 patients with lymphoma of the CNS (8 primary and 3 secondary involvement) were imaged with the CXCR4-directed PET tracer Ga-pentixafor. To evaluate the predictive value of this imaging modality, treatment response, as determined by MRI, was correlated with quantification of CXCR4 expression by Ga-pentixafor PET in vivo before initiation of treatment in 7 of 11 patients. Ga-pentixafor PET showed excellent contrast with the surrounding brain parenchyma in all patients with active disease. Furthermore, initial CXCR4 uptake determined by PET correlated with subsequent treatment response as assessed by MRI. Ga-pentixafor PET represents a novel diagnostic tool for CNS lymphoma with potential implications for theranostic approaches as well as response and risk assessment.
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http://dx.doi.org/10.2967/jnumed.120.241703DOI Listing
December 2020

Development of a Chimeric Antigen-Binding Fragment Directed Against Human Galectin-3 and Validation as an Immuno-Positron Emission Tomography Tracer for the Sensitive Imaging of Thyroid Cancer.

Thyroid 2020 09 30;30(9):1314-1326. Epub 2020 Apr 30.

Klinikum rechts der Isar, Department of Nuclear Medicine, Technical University Munich, Munich, Germany.

The lack of facile methods for the specific characterization of malignant thyroid nodules makes the diagnosis of thyroid cancer (TC) challenging. Due to its restricted expression in such nodules, the cell-associated lectin galectin-3 (Gal3) has emerged as a marker for TC with growing interest for imaging as well as targeted radionuclide therapy. To accelerate translation into clinical application, we have developed a cognate chimeric human antigen-binding fragment (Fab) derived from the rat anti-Gal3 monoclonal antibody M3/38. The variable immunoglobulin (Ig) light and heavy chain sequences were cloned from the hybridoma cell line, and the corresponding Fab carrying human IgG1/κ constant genes was functionally produced in the periplasm of and purified to homogeneity. To moderately prolong its plasma half-life and, thus, increase tumor uptake, the recombinant Fab was fused with a long disordered amino acid chain comprising in total 200 Pro, Ala, and Ser residues (PASylation). This novel tracer was subjected to characterization and validation by using two thyroid cancer orthotopic murine models. To this end, the αGal3-Fab-PAS was conjugated with deferoxamine (Dfo), labeled with Zr under mild conditions and tested for binding on TC cell lines. Athymic nude mice were inoculated either with FRO82-1 or with CAL62 tumor cells into the left thyroid lobe. After intravenous injection with ∼3.0 MBq of Zr-Dfo-PAS-Fab, these mice were subjected to positron emission tomography (PET)/computed tomography imaging followed by quantification of tumor accumulation and immunohistochemical analysis. The αGal3-Fab-PAS revealed high affinity toward the recombinant Gal3 antigen, with a dissociation constant ≤1 nM as measured via enzyme-linked immunosorbent assay, surface plasmon resonance spectroscopy, and radioactive cell binding assay. The Gal3-targeting by the Zr(IV)-labeled protein tracer, as investigated by immuno-PET, demonstrated highly selective and fast accumulation in orthotopically implanted tumors, with strong contrast images achieved 24 hours postinjection, and no uptake in the tumor-free thyroid lobe, as also confirmed by biodistribution studies. The chimeric αGal3 Zr-Dfo-PAS-Fab tracer exhibits selective accumulation in the tumor-bearing thyroid lobe of xenograft mice. Thus, this novel radioactive probe offers potential to change TC management, in addition to current diagnostic procedures, and to reduce unnecessary thyroidectomies.
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http://dx.doi.org/10.1089/thy.2019.0670DOI Listing
September 2020

Dynamic 2D and 3D mapping of hyperpolarized pyruvate to lactate conversion in vivo with efficient multi-echo balanced steady-state free precession at 3 T.

NMR Biomed 2020 06 10;33(6):e4291. Epub 2020 Mar 10.

Department of Radiology, Medical Physics, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

The aim of this study was to acquire the transient MRI signal of hyperpolarized tracers and their metabolites efficiently, for which specialized imaging sequences are required. In this work, a multi-echo balanced steady-state free precession (me-bSSFP) sequence with Iterative Decomposition with Echo Asymmetry and Least squares estimation (IDEAL) reconstruction was implemented on a clinical 3 T positron-emission tomography/MRI system for fast 2D and 3D metabolic imaging. Simulations were conducted to obtain signal-efficient sequence protocols for the metabolic imaging of hyperpolarized biomolecules. The sequence was applied in vitro and in vivo for probing the enzymatic exchange of hyperpolarized [1- C]pyruvate and [1- C]lactate. Chemical shift resolution was achieved using a least-square, iterative chemical species separation algorithm in the reconstruction. In vitro, metabolic conversion rate measurements from me-bSSFP were compared with NMR spectroscopy and free induction decay-chemical shift imaging (FID-CSI). In vivo, a rat MAT-B-III tumor model was imaged with me-bSSFP and FID-CSI. 2D metabolite maps of [1- C]pyruvate and [1- C]lactate acquired with me-bSSFP showed the same spatial distributions as FID-CSI. The pyruvate-lactate conversion kinetics measured with me-bSSFP and NMR corresponded well. Dynamic 2D metabolite mapping with me-bSSFP enabled the acquisition of up to 420 time frames (scan time: 180-350 ms/frame) before the hyperpolarized [1- C]pyruvate was relaxed below noise level. 3D metabolite mapping with a large field of view (180 × 180 × 48 mm ) and high spatial resolution (5.6 × 5.6 × 2 mm ) was conducted with me-bSSFP in a scan time of 8.2 seconds. It was concluded that Me-bSSFP improves the spatial and temporal resolution for metabolic imaging of hyperpolarized [1- C]pyruvate and [1- C]lactate compared with either of the FID-CSI or EPSI methods reported at 3 T, providing new possibilities for clinical and preclinical applications.
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http://dx.doi.org/10.1002/nbm.4291DOI Listing
June 2020

Radiotheranostics: a roadmap for future development.

Lancet Oncol 2020 03;21(3):e146-e156

Department of Radiology, and Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. Electronic address:

Radiotheranostics, injectable radiopharmaceuticals with antitumour effects, have seen rapid development over the past decade. Although some formulations are already approved for human use, more radiopharmaceuticals will enter clinical practice in the next 5 years, potentially introducing new therapeutic choices for patients. Despite these advances, several challenges remain, including logistics, supply chain, regulatory issues, and education and training. By highlighting active developments in the field, this Review aims to alert practitioners to the value of radiotheranostics and to outline a roadmap for future development. Multidisciplinary approaches in clinical trial design and therapeutic administration will become essential to the continued progress of this evolving therapeutic approach.
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http://dx.doi.org/10.1016/S1470-2045(19)30821-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367151PMC
March 2020

Development of a high affinity Anticalin directed against human CD98hc for theranostic applications.

Theranostics 2020 12;10(5):2172-2187. Epub 2020 Jan 12.

Lehrstuhl für Biologische Chemie, Technische Universität München, 85354 Freising, Germany.

Enhanced amino acid supply and dysregulated integrin signaling constitute two hallmarks of cancer and are pivotal for metastatic transformation of cells. In line with its function at the crossroads of both processes, overexpression of CD98hc is clinically observed in various cancer malignancies, thus rendering it a promising tumor target. : We describe the development of Anticalin proteins based on the lipocalin 2 (Lcn2) scaffold against the human CD98hc ectodomain (hCD98hcED) using directed evolution and protein design. X-ray structural analysis was performed to identify the epitope recognized by the lead Anticalin candidate. The Anticalin - with a tuned plasma half-life using PASylation technology - was labeled with Zr and investigated by positron emission tomography (PET) of CD98-positive tumor xenograft mice. : The Anticalin P3D11 binds CD98hc with picomolar affinity and recognizes a protruding loop structure surrounded by several glycosylation sites within the solvent exposed membrane-distal part of the hCD98hcED. studies revealed specific binding activity of the Anticalin towards various CD98hc-expressing human tumor cell lines, suggesting broader applicability in cancer research. PET/CT imaging of mice bearing human prostate carcinoma xenografts using the optimized and Zr-labeled Anticalin demonstrated strong and specific tracer accumulation (8.6 ± 1.1 %ID/g) as well as a favorable tumor-to-blood ratio of 11.8. : Our findings provide a first proof of concept to exploit CD98hc for non-invasive biomedical imaging. The novel Anticalin-based αhCD98hc radiopharmaceutical constitutes a promising tool for preclinical and, potentially, clinical applications in oncology.
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http://dx.doi.org/10.7150/thno.38968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019167PMC
January 2020

Combined DCE-MRI- and FDG-PET enable histopathological grading prediction in a rat model of hepatocellular carcinoma.

Eur J Radiol 2020 Mar 23;124:108848. Epub 2020 Jan 23.

Institute for Diagnostic and Interventional Radiology, Klinikum rechts der Isar der Technischen Universität München, Ismaninger Straße 22, D-81675 München, Germany. Electronic address:

Purpose: To test combined dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-FDG positron emission tomography (FDG-PET)-derived parameters for prediction of histopathological grading in a rat Diethyl Nitrosamine (DEN)-induced hepatocellular carcinoma (HCC) model.

Methods: 15 male Wistar rats, aged 10 weeks were treated with oral DEN 0.01 % in drinking water and monitored until HCCs were detectable. DCE-MRI and PET were performed consecutively on small animal scanners. 38 tumors were identified and manually segmented based on HCC-specific contrast enhancement patterns. Grading (G2/3: 24 tumors, G1:14 tumors) alongside other histopathological parameters, tumor volume, contrast agent and 18F-FDG uptake metrics were noted. Class imbalance was addressed using SMOTE and collinearity was removed using hierarchical clustering and principal component analysis. A logistic regression model was fit separately to the individual parameter groups (DCE-MRI-derived, PET-derived, tumor volume) and the combined parameters.

Results: The combined model using all imaging-derived parameters achieved a mean ± STD sensitivity of 0.88 ± 0.16, specificity of 0.70 ± 0.20 and AUC of 0.90 ± 0.03. No correlation was found between tumor grading and tumor volume, morphology, necrosis, extracellular matrix, immune cell infiltration or underlying liver fibrosis.

Conclusion: A combination of DCE-MRI- and 18F-FDG-PET-derived parameters provides high accuracy for histopathological grading of hepatocellular carcinoma in a relevant translational model system.
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http://dx.doi.org/10.1016/j.ejrad.2020.108848DOI Listing
March 2020

A 3D Deep Residual Convolutional Neural Network for Differential Diagnosis of Parkinsonian Syndromes on F-FDG PET Images.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:3531-3534

Idiopathic Parkinsons disease and atypical parkinsonian syndromes have similar symptoms at early disease stages, which makes the early differential diagnosis difficult. Positron emission tomography with F-FDG shows the ability to assess early neuronal dysfunction of neurodegenerative diseases and is well established for clinical use. In the past decades, machine learning methods have been widely used for the differential diagnosis of parkinsonism based on metabolic patterns. Unlike these conventional machine learning methods relying on hand-crafted features, the deep convolutional neural networks, which have achieved significant success in medical applications recently, have the advantage of learning salient feature representations automatically and effectively. This advantage may offer more appropriate invisible features extracted from data for the enhancement of the diagnosis accuracy. Therefore, this paper develops a 3D deep convolutional neural network on F-FDG PET images for the automated early diagnosis. Furthermore, we depicted in saliency maps the decision mechanism of the deep learning method to assist the physiological interpretation of deep learning performance. The proposed method was evaluated on a dataset with 920 patients. In addition to improving the accuracy in the differential diagnosis of parkinsonism compared to state-of-the-art approaches, the deep learning methods also discovered saliency features in a number of critical regions (e.g., midbrain), which are widely accepted as characteristic pathological regions for movement disorders but were ignored in the conventional analysis of FDG PET images.
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http://dx.doi.org/10.1109/EMBC.2019.8856747DOI Listing
July 2019

Diagnostic performance of quantitative and qualitative parameters for the diagnosis of aortic graft infection using [F]-FDG PET/CT.

J Nucl Cardiol 2020 Jan 6. Epub 2020 Jan 6.

Department of Nuclear Medicine, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany.

Purpose: The aim of this study was the evaluation of quantitative and qualitative parameters for the diagnosis of aortic graft infection (AGI) using [F]-FDG PET/CT.

Methods: PET/CT was performed in 50 patients with clinically suspected AGI. 12 oncological patients with aortic repair but without suspicion of AGI were included in the analysis to serve as control cohort. The [F]-FDG uptake pattern around the graft was assessed using (a) a five-point visual grading scale (VGS), (b) SUV and (c) different graft-to-background ratios (GBRs). The diagnostic performance of VGS, SUV and GBRs was assessed and compared by ROC analysis.

Results: 28 infected and 34 uninfected grafts were identified by standard of reference. SUV and VGS were the most powerful predictors for the diagnosis of AGI according to the area under the curve (AUC 0.988 and 0.983, respectively) without a significant difference compared to GBRs. SUV and VGS showed congruent and accurate findings in 54 patients (i.e. either both positive or negative), yielding sensitivity and specificity (100%) in this subgroup of patients.

Conclusion: Quantitative analysis by SUV and qualitative analysis by VGS are highly effective in the diagnosis of AGI and should be tested as an outcome measure in prospective trials.
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http://dx.doi.org/10.1007/s12350-019-02011-4DOI Listing
January 2020

Radiohybrid Ligands: A Novel Tracer Concept Exemplified by F- or Ga-Labeled rhPSMA Inhibitors.

J Nucl Med 2020 05 20;61(5):735-742. Epub 2019 Dec 20.

Chair of Pharmaceutical Radiochemistry, Technical University of Munich, Garching, Germany; and

When we critically assess the reason for the current dominance of Ga-labeled peptides and peptide-like ligands in radiopharmacy and nuclear medicine, we have to conclude that the major advantage of such radiopharmaceuticals is the apparent lack of suitable F-labeling technologies with proven clinical relevance. To prepare and to subsequently perform a clinical proof-of-concept study on the general suitability of silicon-fluoride-acceptor (SiFA)-conjugated radiopharmaceuticals, we developed inhibitors of the prostate-specific membrane antigen (PSMA) that are labeled by isotopic exchange (IE). To compensate for the pronounced lipophilicity of the SiFA unit, we used metal chelates, conjugated in close proximity to SiFA. Six different radiohybrid PSMA ligands (rhPSMA ligands) were evaluated and compared with the commonly used F-PSMA inhibitors F-DCFPyL and F-PSMA-1007. All inhibitors were synthesized by solid-phase peptide synthesis. Human serum albumin binding was measured by affinity high-performance liquid chromatography, whereas the lipophilicity of each tracer was determined by the -octanol/buffer method. In vitro studies (IC, internalization) were performed on LNCaP cells. Biodistribution studies were conducted on LNCaP tumor-bearing male CB-17 SCID mice. On the laboratory scale (starting activities, 0.2-9.0 GBq), labeling of F-rhPSMA-5 to -10 by IE was completed in < 20 min (radiochemical yields, 58% ± 9%; radiochemical purity, >97%) with molar activities of 12-60 GBq/μmol. All rhPSMAs showed low nanomolar affinity and high internalization by PSMA-expressing cells when compared with the reference radiopharmaceuticals, medium-to-low lipophilicity, and high human serum albumin binding. Biodistribution studies in LNCaP tumor-bearing mice revealed high tumor uptake, sufficiently fast clearance kinetics from blood, low hepatobiliary excretion, fast renal excretion, and very low uptake of F activity in bone. The novel F-rhPSMA radiopharmaceuticals developed under the radiohybrid concept show equal or better targeting characteristics than the established F-PSMA tracers F-DCFPyL and F-PSMA-1007. The unparalleled simplicity of production, the possibility to produce the identical Ga-labeled F-Ga-rhPSMA tracers, and the possibility to extend this concept to true theranostic radiohybrid radiopharmaceuticals, such as F-Lu-rhPSMA, are unique features of these radiopharmaceuticals.
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http://dx.doi.org/10.2967/jnumed.119.234922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198388PMC
May 2020

Room Temperature Al F Labeling of 2-Aminomethylpiperidine-Based Chelators for PET Imaging.

ChemMedChem 2020 02 7;15(3):284-292. Epub 2020 Jan 7.

Department of Nuclear Medicine, Klinikum rechts der Isar TU München, Ismaningerstraße 22, 81675, Munich, Germany.

Positron emission tomography (PET) is a non-invasive molecular imaging technology that is constantly expanding, with a high demand for specific antibody-derived imaging probes. The use of tracers based on temperature-sensitive molecules (i. e. Fab, svFab, nanobodies) is increasing and has led us to design a class of chelators based on the structure of 2-aminomethylpiperidine (AMP) with acetic and/or hydroxybenzyl pendant arms (2-AMPTA, NHB-2-AMPDA, and 2-AMPDA-HB), which were investigated as such for {Al F} -core chelation efficiency. All the compounds were characterized by HPLC-MS analysis and NMR spectroscopy. The AlF-18 labeling reactions were performed under various conditions (pH/temperature), and the radiolabeled chelates were purified and characterized by radio-TLC and radio-HPLC. The stability of labeled chelates was investigated up to 240 min in human serum (HS), EDTA 5 mM, PBS and 0.9 % NaCl solutions. The in vivo stability of [Al F(2-AMPDA-HB)] was assessed in healthy nude mice (n=6). Radiochemical yields between 55 % and 81 % were obtained at pH 5 and room temperature. High stability in HS was measured for [Al F(2-AMPDA-HB)] , with 90 % of F-18 complexed after 120 min. High stability in vivo, rapid hepatobiliary and renal excretion, with low accumulation of free F-18 in bones were measured. Thus, this new Al F-chelator may have a great impact on immuno-PET radiopharmacy, by facilitating the development of new fluorine-18-labeled heat-sensitive biomolecules.
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http://dx.doi.org/10.1002/cmdc.201900652DOI Listing
February 2020

Correction to: In vivo imaging of early stages of rheumatoid arthritis by α5β1-integrin-targeted positron emission tomography.

EJNMMI Res 2019 Dec 11;9(1):107. Epub 2019 Dec 11.

Department of Diagnostic and Interventional Radiology, Technische Universität München, Munich, Germany.

Following publication of the original article [1], the authors have reported an error in the 'Histopathology' (under 'Materials and methods') section of the article that compromises the reproducibility of the paper.
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http://dx.doi.org/10.1186/s13550-019-0582-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906272PMC
December 2019

In vivo imaging of early stages of rheumatoid arthritis by α5β1-integrin-targeted positron emission tomography.

EJNMMI Res 2019 Sep 9;9(1):87. Epub 2019 Sep 9.

Department of Diagnostic and Interventional Radiology, Technische Universität München, Munich, Germany.

Background: Rheumatoid arthritis (RA) is one of the most common rheumatic diseases. Joint inflammation and pathological growth of joint cartilage cause swollen and painful joints, which severely diminishes the patients' life quality. There is no causal treatment. Symptomatic therapies should start as early as possible to take maximal effect. Hence, diagnostic procedures capable of detecting affected joints before the onset of clinical symptoms are highly desirable. We explored the value of PET imaging of integrin subtypes αvβ3 and α5β1 for early detection of RA foci in collagen-induced arthritis (CIA) mouse models.

Results: Development of RA in CIA mice was monitored by paw scoring, and αvβ3- and α5β1-integrin expression was quantified by μPET using Ga-Avebetrin and Ga-Aquibeprin. For consecutive sections of selected decalcified joints (knee, ankle), arthritic degeneration and integrin expression were assessed by MOVAT staining and β3/α5 immunohistochemistry (IHC), respectively. β3- and α5-IHC revealed elevated levels of both αvβ3- and α5β1-integrin in arthritic joints. Unlike αvβ3, α5β1 is strongly expressed in the proliferating synovial lining layer, which suggests that its presence is directly related to RA development. For mice with advanced RA (6 weeks after CIA), PET signals for α5β1-integrin were substantially stronger (> 300% of baseline) than that of αvβ3-integrin (< 200%). A longitudinal PET follow-up revealed that the manifestation of clinical symptoms of RA is preceded by upregulation of α5β1- but not of αvβ3-integrin.

Conclusion: α5β1-integrin PET could add a new functional imaging aspect to the portfolio of RA diagnostics because it appears to be a sensitive biomarker for early RA development. We suggest α5β1-integrin PET as a valuable tool to achieve a higher precision for early diagnosis of RA, including initial staging, monitoring of the disease course, and drug treatment, and for planning of radiosynoviorthesis (RSO).
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http://dx.doi.org/10.1186/s13550-019-0541-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733939PMC
September 2019

What did we learn from PET/MR?

J Nucl Cardiol 2020 06 5;27(3):899-902. Epub 2019 Aug 5.

Department of Nuclear Medicine, Technical University of Munich, Munich, Germany.

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http://dx.doi.org/10.1007/s12350-019-01815-8DOI Listing
June 2020

Report of first recurrent glioma patients examined with PET-MRI prior to re-irradiation.

PLoS One 2019 24;14(7):e0216111. Epub 2019 Jul 24.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.

Background And Purpose: The advantage of combined PET-MRI over sequential PET and MRI is the high spatial conformity and the absence of time delay between the examinations. The benefit of this technique for planning of re-irradiation (re-RT) treatment is unkown yet. Imaging data from a phase 1 trial of re-RT for recurrent glioma was analysed to assess whether planning target volumes and treatment margins in glioma re-RT can be adjusted by PET-MRI with rater independent PET based biological tumour volumes (BTVs).

Patients And Methods: Combined PET-MRI with the tracer O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) prior to re-RT was performed in recurrent glioma patients in a phase I trial. GTVs including all regions suspicious of tumour on contrast enhanced MRI were delineated by three experienced radiation oncologists and included into MRI based consensus GTVs (MRGTVs). BTVs were semi-automatically delineated with a fixed threshold of 1.6 x background activity. Corresponding BTVs and MRGTVs were fused into union volume PET-MRGTVs. The Sørensen-Dice coefficient and the conformity index were used to assess the geometric overlap of the BTVs with the MRGTVs. A recurrence pattern analysis was performed based on the original planning target volumes (PTVs = GTV + 10 mm margin or 5 mm in one case) and the PET-MRGTVs with margins of 10, 8, 5 and 3 mm.

Results: Seven recurrent glioma patients, who received PET-MRI prior to re-RT, were included into the present planning study. At the time of re-RT, patients were in median 54 years old and had a median Karnofsky Performance Status (KPS) score of 80. Median post-recurrence survival after the beginning of re-RT was 13 months. Concomitant bevacizumab therapy was applied in six patients and one patient received chemoradiation with temozolomide. Median GTV volumes of the three radiation oncologists were 35.0, 37.5 and 40.5 cubic centimeters (cc) and median MRGTV volume 41.8 cc. Median BTV volume was 36.6 cc and median PET-MRGTV volume 59.3 cc. The median Sørensen-Dice coefficient for the comparison between MRGTV and BTV was 0.61 and the median conformity index 0.44. Recurrence pattern analysis revealed two central, two in-field and one distant recurrence within both, the original PTV, as well as the PET-MRGTV with a reduced margin of 3 mm.

Conclusion: PET-MRI provides radiation treatment planning imaging with high spatial and timely conformity for high-grade glioma patients treated with re-RT with potential advancements for target volume delineation. Prospective randomised trials are warranted to further investigate the treatment benefits of PET-MRI based re-RT planning.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216111PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6655559PMC
February 2020

F-Fluoroethyl-tyrosine uptake is correlated with amino acid transport and neovascularization in treatment-naive glioblastomas.

Eur J Nucl Med Mol Imaging 2019 Sep 9;46(10):2163-2168. Epub 2019 Jul 9.

Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany.

Purpose: To investigate the in vivo correlation between F-fluoroethyl-tyrosine (F-FET) uptake and amino acid transporter expression and vascularization in treatment-naive glioblastomas.

Methods: A total of 43 stereotactic biopsies were obtained from 13 patients with suspected glioblastoma prior to therapy. All patients underwent a dynamic F-FET PET/MRI scan before biopsy. Immunohistochemistry was performed using antibodies against SLC7A5 (amino acid transporter), MIB-1 (Ki67, proliferation), CD31 (vascularization) and CA-IX (hypoxia). The intensity of staining was correlated with F-FET uptake and the dynamic F-FET uptake slope at the biopsy target point.

Results: In all patients, the final diagnosis was IDH-wildtype glioblastoma, WHO grade IV. Static F-FET uptake was significantly correlated with SLC7A5 staining (r = 0.494, p = 0.001). While the dynamic F-FET uptake slope did not show a significant correlation with amino acid transporter expression, it was significantly correlated with the number of CD31-positive vessels (r = -0.350, p = 0.031), which is line with earlier results linking F-FET kinetics with vascularization and perfusion. Besides, static F-FET uptake also showed correlations with CA-IX staining (r = 0.394, p = 0.009) and CD31 positivity (r = 0.410, p = 0.006). While the correlation between static F-FET uptake and SLC7A5 staining was confirmed as significant in multivariate analysis, this was not the case for the correlation with CD31 positivity, most likely because of the lower effect size and the relatively low number of samples. No significant correlation between F-FET uptake and Ki67 proliferation index was observed in our cohort.

Conclusion: Our results support the findings of preclinical studies suggesting that specific F-FET uptake in glioblastomas is mediated by amino acid transporters. As proposed previously, dynamic F-FET parameters might be more influenced by perfusion and therefore related to properties of the tumour neovascularization.
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http://dx.doi.org/10.1007/s00259-019-04407-3DOI Listing
September 2019

Radiation-Induced Amplification of TGFB1-Induced Mesenchymal Stem Cell-Mediated Sodium Iodide Symporter () Gene I Therapy.

Clin Cancer Res 2019 10 13;25(19):5997-6008. Epub 2019 Jun 13.

Medizinische Klinik und Poliklinik IV-Campus Grosshadern, University Hospital of Munich, Ludwig-Maximilians-University Munich, Munich, Germany.

Purpose: The innate tumor homing potential of mesenchymal stem cells (MSCs) has been used for a targeted delivery of the theranostic sodium iodide symporter () transgene into solid tumors. We have previously shown that external beam radiotherapy (EBRT) results in the enhanced recruitment of expressing MSCs into human hepatocellular carcinoma (HuH7). In parallel, the tumor-associated cytokine TGFB1 becomes strongly upregulated in HuH7 tumors in response to EBRT.

Experimental Design: We therefore evaluated the effects of combining focused EBRT (5 Gy) with MSC-mediated systemic delivery of the theranostic transgene under control of a synthetic TGFB1-inducible SMAD-responsive promoter (SMAD-NIS-MSCs) using I-scintigraphy followed by I therapy in CD1 nu/nu mice harboring subcutaneous human hepatocellular carcinoma (HuH7).

Results: Following tumor irradiation and SMAD-NIS-MSC application, tumoral iodide uptake monitored by I-scintigraphy was enhanced as compared with nonirradiated tumors. Combination of EBRT and SMAD-NIS-MSC-mediated I therapy resulted in a significantly improved delay in tumor growth and prolonged survival in therapy mice as compared with the combined therapy using CMV-NIS-MSCs or to control groups receiving EBRT or saline only, or EBRT together with SMAD-NIS-MSCs and saline applications.

Conclusions: MSC-based NIS-mediated I therapy after EBRT treatment dramatically enhanced therapeutic efficacy when a TGFB1-inducible SMAD-responsive promoter was used to drive expression in adoptively applied MSCs. The remarkable therapeutic effect seen is thought to be linked in large part to the enhanced TGFB1 produced in this context, which leads to a highly selective and focused amplification of MSC-based expression within the tumor milieu.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-4092DOI Listing
October 2019