Publications by authors named "Hans-Jürgen Wester"

280 Publications

CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas.

Diagnostics (Basel) 2021 Mar 29;11(4). Epub 2021 Mar 29.

European Neuroendocrine Tumor Society (ENETS) Center of Excellence, NET Zentrum, University Hospital Würzburg, 97080 Würzburg, Germany.

We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. Ga-Pentixafor visualized tumor lesions in 10/11 subjects, whileF-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, = 107; < 0.001). Semi-quantitative analysis revealed markedly higher F-FDG uptake as compared to Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUV: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUV: 7.4 ± 5.4 vs. 3.1 ± 3.2, < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard F-FDG PET/CT.
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http://dx.doi.org/10.3390/diagnostics11040605DOI Listing
March 2021

Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors?

EJNMMI Radiopharm Chem 2021 Feb 26;6(1):10. Epub 2021 Feb 26.

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

Aim: To investigate whether modifications of prostate-specific membrane antigen (PSMA)-targeted radiolabeled urea-based inhibitors could reduce salivary gland uptake and thus improve tumor-to-salivary gland ratios, several analogs of a high affinity PSMA ligand were synthesized and evaluated in in vitro and in vivo studies.

Methods: Binding motifs were synthesized 'on-resin' or, when not practicable, in solution. Peptide chain elongations were performed according to optimized standard protocols via solid-phase peptide synthesis. In vitro experiments were performed using PSMA LNCaP cells. In vivo studies as well as μSPECT/CT scans were conducted with male LNCaP tumor xenograft-bearing CB17-SCID mice.

Results: PSMA ligands with A) modifications within the central Zn-binding unit, B) proinhibitor motifs and C) substituents & bioisosteres of the P1'-γ-carboxylic acid were synthesized and evaluated. Modifications within the central Zn-binding unit of PSMA-10 (Glu-urea-Glu) provided three compounds. Thereof, only Lu-carbamate I (Lu-3) exhibited high affinity (IC = 7.1 ± 0.7 nM), but low tumor uptake (5.31 ± 0.94% ID/g, 1 h p.i. and 1.20 ± 0.55% ID/g, 24 h p.i.). All proinhibitor motif-based ligands (three in total) exhibited low binding affinities (> 1 μM), no notable internalization and very low tumor uptake (< 0.50% ID/g). In addition, four compounds with P1'-ɣ-carboxylate substituents were developed and evaluated. Thereof, only tetrazole derivative Lu-11 revealed high affinity (IC = 16.4 ± 3.8 nM), but also this inhibitor showed low tumor uptake (3.40 ± 0.63% ID/g, 1 h p.i. and 0.68 ± 0.16% ID/g, 24 h p.i.). Salivary gland uptake in mice remained at an equally low level for all compounds (between 0.02 ± 0.00% ID/g and 0.09 ± 0.03% ID/g), wherefore apparent tumor-to-submandibular gland and tumor-to-parotid gland ratios for the modified peptides were distinctly lower (factor 8-45) than for [Lu]Lu-PSMA-10 at 24 h p.i.

Conclusions: The investigated compounds could not compete with the in vivo characteristics of the EuE-based PSMA inhibitor [Lu]Lu-PSMA-10. Although two derivatives (3 and 11) were found to exhibit high affinities towards LNCaP cells, tumor uptake at 24 h p.i. was considerably low, while uptake in salivary glands remained unaffected. Optimization of the established animal model should be envisaged to enable a clear identification of PSMA-targeting radioligands with improved tumor-to-salivary gland ratios in future studies.
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http://dx.doi.org/10.1186/s41181-021-00124-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910394PMC
February 2021

Improved primary staging of marginal zone lymphoma by addition of CXCR4-directed PET/CT.

J Nucl Med 2021 Feb 12. Epub 2021 Feb 12.

Comprehensive Cancer Center (CCC) Mainfranken, Germany.

Positron emission tomography/computed tomography (PET/CT) with F-fluorodesoxyglucose (FDG) is an integral component in the primary staging of most lymphomas. However, its utility is limited in marginal zone lymphoma (MZL) due to inconsistent FDG avidity. One diagnostic alternative could be the targeting of CXC-motif chemokine receptor 4 (CXCR4), shown to be expressed by MZL cells. This study investigated the value of adding CXCR4-directed Ga-Pentixafor PET/CT to conventional staging. 22 newly diagnosed MZL patients were staged conventionally and with Ga-Pentixafor PET/CT. Lesions exclusively identified by Ga-Pentixafor PET/CT were biopsied as standard of reference and compared to imaging results. The impact of CXCR4-directed imaging on staging results and treatment protocol was assessed. Ga-Pentixafor PET/CT correctly identified all patients with viable MZL and was superior to conventional staging ( < 0.001). CXCR4-directed imaging results were validated by confirmation of MZL in 21/24 PET-guided biopsy samples. Inclusion of Ga-Pentixafor PET/CT in primary staging significantly impacted staging results in almost half, and treatment protocols in one third of patients (upstaging, = 7; downstaging, = 3; treatment change, = 8; < 0.03). Ga-Pentixafor PET/CT is a suitable tool in primary staging of MZL and holds the potential to improve existing diagnostic algorithms.
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http://dx.doi.org/10.2967/jnumed.120.257279DOI Listing
February 2021

[Ga]Ga-Pentixafor for PET Imaging of Vascular Expression of CXCR-4 as a Marker of Arterial Inflammation in HIV-Infected Patients: A Comparison with F[FDG] PET Imaging.

Biomolecules 2020 12 3;10(12). Epub 2020 Dec 3.

Department of Nuclear Medicine, University of Pretoria, Pretoria 0001, South Africa.

People living with human immunodeficiency virus (PLHIV) have excess risk of atherosclerotic cardiovascular disease (ASCVD). Arterial inflammation is the hallmark of atherogenesis and its complications. In this study we aimed to perform a head-to-head comparison of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([F]FDG PET/CT) and Gallium-68 pentixafor positron emission tomography/computed tomography [Ga]Ga-pentixafor PET/CT for quantification of arterial inflammation in PLHIV. We prospectively recruited human immunodeficiency virus (HIV)-infected patients to undergo [F]FDG PET/CT and [Ga]Ga-pentixafor PET/CT within two weeks of each other. We quantified the levels of arterial tracer uptake on both scans using maximum standardized uptake value (SUVmax) and target-background ratio. We used Bland and Altman plots to measure the level of agreement between tracer quantification parameters obtained on both scans. A total of 12 patients were included with a mean age of 44.67 ± 7.62 years. The mean duration of HIV infection and mean CD+ T-cell count of the study population were 71.08 ± 37 months and 522.17 ± 260.33 cells/µL, respectively. We found a high level of agreement in the quantification variables obtained using [F]FDG PET and [Ga]Ga-pentixafor PET. There is a good level of agreement in the arterial tracer quantification variables obtained using [F]FDG PET/CT and [Ga]Ga-pentixafor PET/CT in PLHIV. This suggests that [Ga]Ga-pentixafor may be applied in the place of [F]FDG PET/CT for the quantification of arterial inflammation.
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http://dx.doi.org/10.3390/biom10121629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761707PMC
December 2020

Preclinical comparison of four [F, Ga]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics.

EJNMMI Res 2020 Dec 7;10(1):149. Epub 2020 Dec 7.

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

Introduction: Radiohybrid (rh) ligands, a novel class of prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals, can be labeled either with [F]fluorine via isotopic exchange or with radiometals (such as [Ga]Gallium, [Lu]Lutetium, [Ac]Actinium). Among these, [F, Ga]rhPSMA-7 has recently entered clinical assessment.

Aim: Since [F, Ga]rhPSMA-7 is composed of four stereoisomers ([F, Ga]rhPSMA-7.1, -7.2, -7.3 and -7.4), we initiated a preclinical selection process to identify the isomer with the most favorable pharmacokinetics for further clinical investigation.

Methods: A synthetic protocol for enantiopure [F, Ga]rhPSMA-7 isomers has been developed. The comparative evaluation of the four isomers comprised human serum albumin binding, lipophilicity, IC, internalization and classical biodistribution studies and competition experiments in LNCaP tumor-bearing CB-17 SCID mice. In addition, a radio high-performance liquid chromatography-based method was developed allowing quantitative, intraindividual comparison of [F, Ga]rhPSMA-7.1 to -7.4 in LNCaP tumor-bearing mice.

Results: Cell studies revealed high PSMA affinity and internalization for [F, Ga]rhPSMA-7.2, -7.3 and -7.4, whereas [F, Ga]rhPSMA-7.1 showed approximately twofold lower values. Although the biodistribution profile obtained was typical of PSMA inhibitors, it did not allow for selection of a lead candidate for clinical studies. Thus, an intraindividual comparison of all four isomers in LNCaP tumor-bearing mice was carried out by injection of a diastereomeric mixture, followed by analysis of the differential uptake and excretion pattern of each isomer. Based on its high tumor accumulation and low uptake in blood, liver and kidneys, [F, Ga]rhPSMA-7.3 was identified as the preferred isomer and transferred into clinical studies.

Conclusion: [F, Ga]rhPSMA-7.3 has been selected as a lead compound for clinical development of a [F]rhPSMA-based candidate. The intraindividual differential uptake and excretion analysis in vivo allowed for an accurate comparison and assessment of radiopharmaceuticals.
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http://dx.doi.org/10.1186/s13550-020-00740-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721954PMC
December 2020

At the bench: Pre-clinical evidence for multiple functions of CXCR4 in cancer.

J Leukoc Biol 2020 Oct 26. Epub 2020 Oct 26.

Polyphor Ltd, Allschwil, Switzerland.

Signaling through chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) regulates essential processes in normal physiology, including embryogenesis, tissue repair, angiogenesis, and trafficking of immune cells. Tumors co-opt many of these fundamental processes to directly stimulate proliferation, invasion, and metastasis of cancer cells. CXCR4 signaling contributes to critical functions of stromal cells in cancer, including angiogenesis and multiple cell types in the tumor immune environment. Studies in animal models of several different types of cancers consistently demonstrate essential functions of CXCR4 in tumor initiation, local invasion, and metastasis to lymph nodes and distant organs. Data from animal models support clinical observations showing that integrated effects of CXCR4 on cancer and stromal cells correlate with metastasis and overall poor prognosis in >20 different human malignancies. Small molecules, Abs, and peptidic agents have shown anticancer efficacy in animal models, sparking ongoing efforts at clinical translation for cancer therapy. Investigators also are developing companion CXCR4-targeted imaging agents with potential to stratify patients for CXCR4-targeted therapy and monitor treatment efficacy. Here, pre-clinical studies demonstrating functions of CXCR4 in cancer are reviewed.
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http://dx.doi.org/10.1002/JLB.2BT1018-715RRDOI Listing
October 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 2021 Apr 24;48(4):1070-1080. 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
April 2021

Clinical Molecular Imaging of Pulmonary CXCR4 Expression to Predict Outcome of Pirfenidone Treatment in Idiopathic Pulmonary Fibrosis.

Chest 2021 Mar 19;159(3):1094-1106. Epub 2020 Aug 19.

Department of Pulmonology, Hannover Medical School, Hannover, Germany; Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany; DZL-BREATH, Hannover, Germany. Electronic address:

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive disease for which two antifibrotic drugs recently were approved. However, an unmet need exists to predict responses to antifibrotic treatment, such as pirfenidone. Recent data suggest that upregulated expression of CXCR4 is indicative of outcomes in IPF.

Research Question: Can quantitative, molecular imaging of pulmonary CXCR4 expression as a biomarker for disease activity predict response to the targeted treatment pirfenidone and prognosis in patients with IPF?

Study Design And Methods: CXCR4 expression was analyzed by immunohistochemistry examination of lung tissues and reverse-transcriptase polymerase chain reaction analysis of BAL. PET-CT scanning with the specific CXCR4 ligand Ga-pentixafor was performed in 28 IPF patients and compared with baseline clinical characteristics. In 16 patients, a follow-up scan was obtained 6 to 12 weeks after initiation of treatment with pirfenidone. Patients were followed up in our outpatient clinic for ≥ 12 months.

Results: Immunohistochemistry analysis showed high CXCR4 staining of epithelial cells and macrophages in areas with vast fibrotic remodeling. Targeted PET scanning revealed CXCR4 upregulation in fibrotic areas of the lungs, particularly in zones with subpleural honeycombing. Baseline CXCR4 signal demonstrated a significant correlation with Gender Age Physiology stage (r = 0.44; P = .02) and with high-resolution CT scan score (r = 0.38; P = .04). Early changes in CXCR4 signal after initiation of pirfenidone treatment correlated with the long-term course of FVC after 12 months (r = -0.75; P = .0008). Moreover, patients with a high pulmonary CXCR4 signal on follow-up PET scan after 6 weeks into treatment demonstrated a statistically significant worse outcome at 12 months (P = .002). In multiple regression analysis, pulmonary CXCR4 signal on follow-up PET scan emerged as the only independent predictor of long-term outcome (P = .0226).

Interpretation: CXCR4-targeted PET imaging identified disease activity and predicted outcome of IPF patients treated with pirfenidone. It may serve as a future biomarker for personalized guidance of antifibrotic treatment.
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http://dx.doi.org/10.1016/j.chest.2020.08.2043DOI Listing
March 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

In Human Visualization of Ibrutinib-Induced CLL Compartment Shift.

Cancer Immunol Res 2020 08 24;8(8):984-989. Epub 2020 Jun 24.

Division of Hematology, Department of Medicine I, Medical University of Vienna, Vienna, Austria.

Bruton tyrosine kinase inhibitor ibrutinib is effective in treating chronic lymphocytic leukemia (CLL). However, after ibrutinib treatment initiation, patients frequently experience an increase of CLL blood cell count. This phenomenon in clinical practice is thought to reflect a "compartment shift" of CLL cells from lymph nodes to the peripheral blood, but the actual shifting has not yet been demonstrated. Using [Ga]Pentixafor-PET/MRI for CXCR4 visualization, we here provide images of topical changes of CLL cells upon ibrutinib treatment. Within the first month of ibrutinib treatment, mean standardized [Ga]Pentixafor uptake decreased in the bone marrow and lymph nodes, whereas [Ga]Pentixafor uptake increased in the spleen. Leukocytosis rose, as did numbers of CXCR4 (tissue-resident) CLL cells. Volumes of lymph nodes and spleen decreased. Upon longer ibrutinib treatment, leukocytosis decreased, followed by a decrease of [Ga]Pentixafor uptake in the spleen. These results support the preexisting clinical hypothesis of a "compartment shift" of CLL cells from the lymph nodes to the peripheral blood, but also refine the mechanistic model by describing early clearing of the bone marrow and redistribution of CLL cells to the orthotopic splenic cavernous system in response to ibrutinib treatment.
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http://dx.doi.org/10.1158/2326-6066.CIR-19-0880DOI Listing
August 2020

[Ga]-NODAGA-RGD Positron Emission Tomography (PET) for Assessment of Post Myocardial Infarction Angiogenesis as a Predictor for Left Ventricular Remodeling in Mice after Cardiac Stem Cell Therapy.

Cells 2020 05 30;9(6). Epub 2020 May 30.

Department of Nuclear Medicine, Rostock University Medical Center, 18057 Rostock, Germany.

Angiogenesis plays a central role in the healing process following acute myocardial infarction. The PET tracer [Ga]-NODAGA-RGD, which is a ligand for the αβ integrin, has been investigated for imaging angiogenesis in the process of healing myocardium in both animal and clinical studies. It´s value as a prognostic marker of functional outcome remains unclear. Therefore, the aim of this work was to establish [Ga]-NODAGA-RGD for imaging angiogenesis in the murine infarct model and evaluate the tracer as a predictor for cardiac remodeling in the context of cardiac stem cell therapy. [Ga]-NODAGA-RGD PET performed seven days after left anterior descending coronary artery (LAD) occlusion in 129S6 mice showed intense tracer accumulation within the infarct region. The specificity was shown in a sub-group of animals by application of the competitive inhibitor cilengitide prior to tracer injection in a subgroup of animals. Myocardial infarction (MI) significantly reduced cardiac function and resulted in pronounced left ventricular remodeling after three weeks, as measured by cardiac MRI in a separate group. Cardiac induced cells (CiC) that were derived from mESC injected intramyocardially in the therapy group significantly improved left ventricular ejection fraction (LVEF). Surprisingly, CiC transplantation resulted in significantly lower tracer accumulation seven days after MI induction. Accordingly, we successfully established the PET tracer [Ga]-NODAGA-RGD for the assessment of αβ integrin expression in the healing process after MI in the mouse model. Yet, our results indicate that the mere extent of angiogenesis following MI does not serve as a sufficient prognostic marker for functional outcome.
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http://dx.doi.org/10.3390/cells9061358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349714PMC
May 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

Mapping the Binding Interface of PET Tracer Molecules and Alzheimer Disease Aβ Fibrils by Using MAS Solid-State NMR Spectroscopy.

Chembiochem 2020 Sep 19;21(17):2495-2502. Epub 2020 May 19.

Munich Center for Integrated Protein Science (CIPS-M) Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747, Garching, Germany.

Positron emission tomography (PET) tracer molecules like thioflavin T specifically recognize amyloid deposition in brain tissue by selective binding to hydrophobic or aromatic surface grooves on the β-sheet surface along the fibril axis. The molecular basis of this interaction is, however, not well understood. We have employed magic angle spinning (MAS) solid-state NMR spectroscopy to characterize Aβ-PET tracer complexes at atomic resolution. We established a titration protocol by using bovine serum albumin as a carrier to transfer hydrophobic small molecules to Aβ(1-40) fibrillar aggregates. The same Aβ(1-40) amyloid fibril sample was employed in subsequent titrations to minimize systematic errors that potentially arise from sample preparation. In the experiments, the small molecules C-methylated Pittsburgh compound B (PiB) as well as a novel Aβ tracer based on a diarylbithiazole (DABTA) scaffold were employed. Classical C-detected as well as proton-detected spectra of protonated and perdeuterated samples with back-substituted protons, respectively, were acquired and analyzed. After titration of the tracers, chemical-shift perturbations were observed in the loop region involving residues Gly25-Lys28 and Ile32-Gly33, thus suggesting that the PET tracer molecules interact with the loop region connecting β-sheets β1 and β2 in Aβ fibrils. We found that titration of the PiB derivatives suppressed fibril polymorphism and stabilized the amyloid fibril structure.
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http://dx.doi.org/10.1002/cbic.202000143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496087PMC
September 2020

The effect of ligand amount, affinity and internalization on PSMA-targeted imaging and therapy: A simulation study using a PBPK model.

Sci Rep 2019 12 27;9(1):20041. Epub 2019 Dec 27.

Medical Radiation Physics, Department of Nuclear Medicine, Ulm University, Ulm, Germany.

The aim of this work was to investigate the effect of ligand amount, affinity and internalization of prostate-specific membrane antigen (PSMA)-specific ligands on the activity concentrations for PET/CT imaging and on the absorbed doses for therapy. A physiologically-based pharmacokinetic (PBPK) model for PSMA-specific ligands was implemented. Thirteen virtual patients with metastatic castration-resistant prostate cancer were analysed. Simulations were performed for different combinations of association rates k (0.1-0.01 L/nmol/min), dissociation rates k (0.1-0.0001 min), internalization rates λ (0.01-0.0001 min) and ligand amounts (1-1000 nmol). For imaging the activity was normalized to volume and injected activity (Ga-PSMA at 1 h). For therapy the absorbed dose was calculated for 7.3 ± 0.3 GBq Lu-PSMA. The effect of the investigated parameters on therapy were larger compared to imaging. For imaging, the combination of properties leading to the highest tumour uptake was k = 0.1 L/nmol/min, k = 0.01 min for typical ligand amounts (1-10 nmol). For therapy, the higher the internalization rate, the larger was the required ligand amount for optimal tumour-to-kidney ratios. The higher the affinity, the more important was the choice of the optimal ligand amount. PBPK modelling provides insight into the pharmacokinetics of PSMA-specific ligands. Further in silico and in vivo studies are required to verify the influence of the analysed parameters.
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http://dx.doi.org/10.1038/s41598-019-56603-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934468PMC
December 2019

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

Image-Guided Surgery: Are We Getting the Most Out of Small-Molecule Prostate-Specific-Membrane-Antigen-Targeted Tracers?

Bioconjug Chem 2020 02 6;31(2):375-395. Epub 2020 Jan 6.

Interventional Molecular Imaging Laboratory, Department of Radiology , Leiden University Medical Center , 2333 ZA Leiden , The Netherlands.

Expressed on virtually all prostate cancers and their metastases, the transmembrane protein prostate-specific membrane antigen (PSMA) provides a valuable target for the imaging of prostate cancer. Not only does PSMA provide a target for noninvasive diagnostic imaging, e.g., PSMA-positron emission tomography (PSMA-PET), it can also be used to guide surgical resections of PSMA-positive lesions. The latter characteristic has led to the development of a plethora of PSMA-targeted tracers, i.e., radiolabeled, fluorescent, or hybrid. With image-guided surgery applications in mind, this review discusses these compounds based on clinical need. Here, the focus is on the chemical aspects (e.g., imaging label, spacer moiety, and targeting vector) and their impact on in vitro and in vivo tracer characteristics (e.g., affinity, tumor uptake, and clearance pattern).
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033908PMC
February 2020

Quantitative and Qualitative Analyses of Biodistribution and PET Image Quality of a Novel Radiohybrid PSMA, F-rhPSMA-7, in Patients with Prostate Cancer.

J Nucl Med 2020 05 13;61(5):702-709. Epub 2019 Dec 13.

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

Radiohybrid PSMA (rhPSMA) ligands, a new class of theranostic prostate-specific membrane antigen (PSMA)-targeting agents, feature fast F synthesis and utility for labeling with radiometals. Here, we assessed the biodistribution and image quality of F-rhPSMA-7 to determine the best imaging time point for patients with prostate cancer. In total, 202 prostate cancer patients who underwent a clinically indicated F-rhPSMA-7 PET/CT were retrospectively analyzed, and 12 groups based on the administered activity and uptake time of PET scanning were created: 3 administered activities (low, 222-296 MBq; moderate, 297-370 MBq; and high, 371-444 MBq) and 4 uptake time points (short, 50-70 min; intermediate, 71-90 min; long, 91-110 min; and extra long, ≥111 min). For quantitative analyses, SUV and organ- or tumor-to-background ratio were determined for background, healthy organs, and 3 representative tumor lesions. Qualitative analyses assessed overall image quality, nonspecific blood-pool activity, and background uptake in bone or marrow using 3- or 4-point scales. In quantitative analyses, SUV showed a significant decrease in the blood pool and lungs and an increase in the kidneys, bladder, and bones as the uptake time increased. SUV showed a trend to increase in the blood pool and bones as the administered activity increased. However, no significant differences were found in 377 tumor lesions with respect to the administered activity or uptake time. In qualitative analyses, the overall image quality was stable along with the uptake time, but the proportion rated to have good image quality decreased as the administered activity increased. All other qualitative image parameters showed no significant differences for the administered activities, but they showed significant trends with increasing uptake time: less nonspecific blood activity, more frequent background uptake in the bone marrow, and increased negative impact on clinical decision making. The biodistribution of F-rhPSMA-7 was similar to that of established PSMA ligands, and tumor uptake of F-rhPSMA-7 was stable across the administered activities and uptake times. An early imaging time point (50-70 min) is recommended for F-rhPSMA-7 PET/CT to achieve the highest overall image quality.
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http://dx.doi.org/10.2967/jnumed.119.234609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198378PMC
May 2020

F-rhPSMA-7 PET for the Detection of Biochemical Recurrence of Prostate Cancer After Radical Prostatectomy.

J Nucl Med 2020 05 13;61(5):696-701. Epub 2019 Dec 13.

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

F-labeled prostate-specific membrane antigen (PSMA) PET tracers are increasingly used in preference to Ga-PSMA-11 for restaging biochemical recurrence (BCR) of prostate cancer. They are associated with longer half-lives, larger-scale production, and lower positron range than their Ga-labeled counterparts. Here, we describe the efficacy of an F-labeled radiohybrid PSMA, rhPSMA-7, a novel theranostic PSMA-targeting agent for imaging BCR of prostate cancer. Datasets from 261 consecutive patients with noncastrate BCR after radical prostatectomy who underwent F-rhPSMA-7 PET/CT at our institution between June 2017 and March 2018 were reviewed retrospectively. All lesions suspected of being recurrent prostate cancer were recorded. The detection rate for sites of presumed recurrence was correlated with patients' prostate-specific antigen (PSA) level, primary Gleason score, and prior therapy (androgen deprivation therapy and external-beam radiation therapy). The 261 patients had a median PSA level of 0.96 ng/mL (range, 0.01-400 ng/mL). The median injected activity of F-rhPSMA-7 was 336 MBq, with a median uptake time of 76 min. In total, 211 patients (81%) showed pathologic findings on F-rhPSMA-7 PET/CT. The detection rates were 71% (42/59), 86% (44/51), 86% (42/49), and 95% (76/80) at PSA levels of 0.2 to <0.5 ng/mL, 0.5 to <1 ng/mL, 1 to <2 ng/mL, and ≥2 ng/mL, respectively. In 32% patients (7/22) with a PSA of less than 0.2 ng/mL, suggestive lesions were present. F-rhPSMA-7 PET/CT revealed local recurrence in 43% of patients (113). Lymph node metastases were present in the pelvis in 42% of patients (110), in the retroperitoneum in 17% (45), and in a supradiaphragmatic location in 8.0% (21). Bone and visceral metastases were detected in 21% (54) and 3.8% (10), respectively. Detection efficacy was not influenced by prior external-beam radiation therapy (79.1% vs. 82.1%, = 0.55), androgen deprivation therapy within the 6 mo preceding imaging (80.6% vs. 80.9%, = 0.54), or primary Gleason score (77.9% for ≤7 vs. 82.6% for ≥8, = 0.38). F-rhPSMA-7 PET/CT offers high detection rates in early BCR after radical prostatectomy, especially among patients with low PSA values.
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http://dx.doi.org/10.2967/jnumed.119.234914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198386PMC
May 2020

Histologically Confirmed Diagnostic Efficacy of F-rhPSMA-7 PET for N-Staging of Patients with Primary High-Risk Prostate Cancer.

J Nucl Med 2020 05 13;61(5):710-715. Epub 2019 Dec 13.

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

F-rhPSMA-7 (radiohybrid prostate-specific membrane antigen [PSMA]) is a novel ligand for PET imaging. Here, we present data from a retrospective analysis using PET/CT and PET/MRI examinations to investigate the efficacy of F-rhPSMA-7 PET for primary N-staging of patients with prostate cancer (PC) compared with morphologic imaging (CT or MRI) and validated by histopathology. Data from 58 patients with high-risk PC (according to the D'Amico criteria) who were staged with F-rhPSMA-7 PET/CT or PET/MRI at our institution between July 2017 and June 2018 were reviewed. The patients had a median prescan prostate-specific antigen value of 12.2 ng/mL (range, 1.2-81.6 ng/mL). The median injected activity of F-rhPSMA-7 was 327 MBq (range, 132-410 MBq), with a median uptake time of 79.5 min (range, 60-153 min). All patients underwent subsequent radical prostatectomy and extended pelvic lymph node dissection. The presence of lymph node metastases was determined by an experienced reader independently for both the PET and the morphologic datasets using a template-based analysis on a 5-point scale. Patient-level and template-based results were both compared with histopathologic findings. Lymph node metastases were present in 18 patients (31.0%) and were located in 52 of 375 templates (13.9%). Receiver-operating-characteristic analyses showed F-rhPSMA-7 PET to perform significantly better than morphologic imaging on both patient-based and template-based analyses (areas under curve, 0.858 vs. 0.649 [ = 0.012] and 0.765 vs. 0.589 [ < 0.001], respectively). On patient-based analyses, the sensitivity, specificity, and accuracy of F-rhPSMA-7 PET were 72.2%, 92.5%, and 86.2%, respectively, and those of morphologic imaging were 50.0%, 72.5%, and 65.5%, respectively. On template-based analyses, the sensitivity, specificity, and accuracy of F-rhPSMA-7 PET were 53.8%, 96.9%, and 90.9%, respectively, and those of morphologic imaging were 9.6%, 95.0%, and 83.2%, respectively. F-rhPSMA-7 PET is superior to morphologic imaging for N-staging of high-risk primary PC. The efficacy of F-rhPSMA-7 is similar to published data for Ga-PSMA-11.
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http://dx.doi.org/10.2967/jnumed.119.234906DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198390PMC
May 2020

Prostate-Specific Membrane Antigen-Guided Surgery.

J Nucl Med 2020 01 15;61(1):6-12. Epub 2019 Nov 15.

Department of Urology, Antoni van Leeuwenhoek Hospital-The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Since its introduction to the diagnostic pathway for prostate cancer management, prostate-specific membrane antigen (PSMA)-ligand PET has demonstrated great potential. PSMA-ligand imaging is increasingly influencing therapeutic decision making, although its impact on patient outcomes still needs to be defined. One relatively new application, enabled through chemical and engineering efforts, is PSMA-guided surgery. This review highlights the potential of PSMA-guided surgery and discusses its implications in lymph node dissection in primary and recurrent prostate cancer.
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http://dx.doi.org/10.2967/jnumed.119.232330DOI Listing
January 2020

Trending: Radioactive and Fluorescent Bimodal/Hybrid Tracers as Multiplexing Solutions for Surgical Guidance.

J Nucl Med 2020 01 11;61(1):13-19. Epub 2019 Nov 11.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

By contributing to noninvasive molecular imaging and radioguided surgery, nuclear medicine has been instrumental in the realization of precision medicine. During the last decade, it has also become apparent that nuclear medicine (e.g., in the form of bimodal/hybrid tracers) can help to empower fluorescence-guided surgery. More specifically, when using hybrid tracers, lesions can be noninvasively identified and localized with a high sensitivity and precision (guided by the radioisotope) and ultimately resected under real-time optical guidance (fluorescent dye). This topical review discusses early clinical successes, preclinical directions, and key aspects that could have an impact on the future of this field.
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http://dx.doi.org/10.2967/jnumed.119.228684DOI Listing
January 2020

Dissecting the target leukocyte subpopulations of clinically relevant inflammation radiopharmaceuticals.

J Nucl Cardiol 2019 Oct 28. Epub 2019 Oct 28.

Department of Nuclear Medicine, Hannover Medical School, Carl Neuberg-Str. 1, 30625, Hannover, Germany.

Background: Leukocyte subtypes bear distinct pro-inflammatory, reparative, and regulatory functions. Imaging inflammation provides information on disease prognosis and may guide therapy, but the cellular basis of the signal remains equivocal. We evaluated leukocyte subtype specificity of characterized clinically relevant inflammation-targeted radiotracers.

Methods And Results: Leukocyte populations were purified from blood- and THP-1-derived macrophages were polarized into M1-, reparative M2a-, or M2c-macrophages. In vitro uptake assays were conducted using tracers of enhanced glucose or amino acid metabolism and molecular markers of inflammatory cells. Both F-deoxyglucose (F-FDG) and the labeled amino acid C-methionine (C-MET) displayed higher uptake in neutrophils and monocytes compared to other leukocytes (P = 0.005), and markedly higher accumulation in pro-inflammatory M1-macrophages compared to reparative M2a-macrophages (P < 0.001). Molecular tracers Ga-DOTATATE targeting the somatostatin receptor type 2 and Ga-pentixafor targeting the chemokine receptor type 4 (CXCR4) exhibited broad uptake by leukocyte subpopulations and polarized macrophages with highest uptake in T-cells/natural killer cells and B-cells compared to neutrophils. Mitochondrial translocator protein (TSPO)-targeted F-flutriciclamide selectively accumulated in monocytes and pro-inflammatory M1 macrophages (P < 0.001). Uptake by myocytes and fibroblasts tended to be higher for metabolic radiotracers.

Conclusions: The different in vitro cellular uptake profiles may allow isolation of distinct phases of the inflammatory pathway with specific inflammation-targeted radiotracers. The pathogenetic cell population in specific inflammatory diseases should be considered in the selection of an appropriate imaging agent.
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http://dx.doi.org/10.1007/s12350-019-01929-zDOI Listing
October 2019

Imaging Inflammation in Atherosclerosis with CXCR4-Directed Ga-Pentixafor PET/CT: Correlation with F-FDG PET/CT.

J Nucl Med 2020 05 25;61(5):751-756. Epub 2019 Oct 25.

Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.

C-X-C motif chemokine receptor 4 (CXCR4) is expressed on the surface of various cell types involved in atherosclerosis, with a particularly rich receptor expression on macrophages and T cells. First pilot studies with Ga-pentixafor, a novel CXCR4-directed PET tracer, have shown promise to noninvasively image inflammation within atherosclerotic plaques. The aim of this retrospective study was to investigate the performance of Ga-pentixafor PET/CT for imaging atherosclerosis in comparison to F-FDG PET/CT. Ninety-two patients (37 women and 55 men; mean age, 62 ± 10 y) underwent Ga-pentixafor and F-FDG PET/CT for staging of oncologic diseases. In these subjects, lesions in the walls of large arteries were identified using morphologic and PET criteria for atherosclerosis ( = 652). Tracer uptake was measured and adjusted for vascular lumen (background) signal by calculation of target-to-background ratios (TBRs) by 2 investigators masked to the other PET scan. On a lesion-to-lesion and patient basis, the TBRs of both PET tracers were compared and additionally correlated to the degree of arterial calcification as quantified in CT. On a lesion-to-lesion basis, Ga-pentixafor and F-FDG uptake showed a weak correlation ( = 0.28; < 0.01). Ga-pentixafor PET identified more lesions ( = 290; TBR ≥ 1.6, < 0.01) and demonstrated higher uptake than F-FDG PET (1.8 ± 0.5 vs. 1.4 ± 0.4; < 0.01). The degree of plaque calcification correlated negatively with both Ga-pentixafor and F-FDG uptake ( = -0.38 vs. -0.31, both < 0.00001). CXCR4-directed imaging of the arterial wall with Ga-pentixafor PET/CT identified more lesions than F-FDG PET/CT, with only a weak correlation between tracers. Further studies to elucidate the underlying biologic mechanisms and sources of CXCR4 positivity, and to investigate the clinical utility of chemokine receptor-directed imaging of atherosclerosis, are highly warranted.
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http://dx.doi.org/10.2967/jnumed.119.234484DOI Listing
May 2020

Ga-PSMA I&T PET/CT for primary staging of prostate cancer.

Eur J Nucl Med Mol Imaging 2020 01 16;47(1):168-177. Epub 2019 Sep 16.

Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Str. 6, 97080, Würzburg, Germany.

Purpose: The present study is based on a retrospective analysis of Gallium-68 (Ga)-labelled prostate-specific membrane antigen (Ga-PSMA I&T) PET/CT performed in newly diagnosed, treatment-naïve prostate cancer (PCa) patients prior to definitive treatment.

Methods: A total of 82 men were included in the study and were imaged with Ga-PSMA I&T PET/CT to assess the distribution of PSMA-avid disease for staging purposes (11 with low-risk, 32 with intermediate-risk, and 39 with high-risk PCa). Forty patients (20 with intermediate- and 20 with high-risk disease) underwent subsequent radical prostatectomy with extended pelvic lymph node dissection which allowed for correlation of imaging findings with histopathologic data.

Results: PSMA-positive disease was detected in 83% of patients with 66/82 (80.5%) primary tumours being visualized. PSMA-avid lymph nodes were recorded in 17/82 patients (20.7%, 3 with intermediate-risk and 14 with high-risk PCa); distant disease was found in 14/82 subjects (17.1%, 2 with intermediate-risk and 12 with high-risk PCa). No extraprostatic disease was found in low-risk PCa. SUV of primary tumours showed a weak but significant correlation with serum PSA values (r = 0.51, p < 0.001) and Gleason scores (GSC; r = 0.35, p = 0.001), respectively. In correlation with histopathology, calculated per-region sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detection of lymph node metastases were 35.0%, 98.4%, 63.6%, 95.0%, and 93.0%, respectively.

Conclusions: In patients with initial diagnosis of intermediate- and high-risk prostate cancer, Ga-PSMA I&T PET/CT emerges as a relevant staging procedure by identifying nodal and/or distant metastases. Due to the low prevalence of extraprostatic disease, its value seems to be limited in low-risk disease.
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http://dx.doi.org/10.1007/s00259-019-04524-zDOI Listing
January 2020

Hybrid Tracers Based on Cyanine Backbones Targeting Prostate-Specific Membrane Antigen: Tuning Pharmacokinetic Properties and Exploring Dye-Protein Interaction.

J Nucl Med 2020 02 3;61(2):234-241. Epub 2019 Sep 3.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

Prostate cancer surgery is currently being revolutionized by the use of prostate-specific membrane antigen (PSMA)-targeted radiotracers, for example, Tc-labeled PSMA tracer analogs for radioguided surgery. The purpose of this study was to develop a second-generation Tc-labeled PSMA-targeted tracer incorporating a fluorescent dye. Several PSMA-targeted hybrid tracers were synthesized: glutamic acid-urea-lysine (EuK)-Cy5-mas, EuK-(SO)Cy5-mas, EuK-Cy5(SO)-mas, EuK-(Ar)Cy5-mas, and EuK-Cy5(Ar)-mas; the Cy5 dye acts as a functional backbone between the EuK targeting vector and the 2-mercaptoacetyl-seryl-seryl-seryl (mas) chelate to study the dye's interaction with PSMA's amphipathic entrance funnel. The compounds were evaluated for their photophysical and chemical properties and PSMA affinity. After radiolabeling with Tc, we performed in vivo SPECT imaging, biodistribution, and fluorescence imaging on BALB/c nude mice with orthotopically transplanted PC346C tumors. The dye composition influenced the photophysical properties (brightness range 0.3-1.5 × 10 M × cm), plasma protein interactions (range 85.0% ± 2.3%-90.7% ± 1.3% bound to serum, range 76% ± 0%-89% ± 6% stability in serum), PSMA affinity (half-maximal inhibitory concentration [IC] range 19.2 ± 5.8-175.3 ± 61.1 nM) and in vivo characteristics (tumor-to-prostate and tumor-to-muscle ratios range 0.02 ± 0.00-154.73 ± 28.48 and 0.46 ± 0.28-5,157.50 ± 949.17, respectively; renal, splenic, and salivary retention). Even though all tracer analogs allowed tumor identification with SPECT and fluorescence imaging, Tc-EuK-(SO)Cy5-mas had the most promising properties (e.g., half-maximal inhibitory concentration, 19.2 ± 5.8, tumor-to-muscle ratio, 5,157.50 ± 949.17). Our findings demonstrate the intrinsic integration of a fluorophore in the pharmacophore in PSMA-targeted small-molecule tracers. In this design, having 1 sulfonate on the indole moiety adjacent to EuK (Tc-EuK-(SO)Cy5-mas) yielded the most promising tracer candidate for imaging of PSMA.
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http://dx.doi.org/10.2967/jnumed.119.233064DOI Listing
February 2020

CXCR4-Directed Imaging in Solid Tumors.

Front Oncol 2019 14;9:770. Epub 2019 Aug 14.

Department of Nuclear Medicine, University of Wuerzburg, Wuerzburg, Germany.

Despite histological evidence in various solid tumor entities, available experience with CXCR4-directed diagnostics and endoradiotherapy mainly focuses on hematologic diseases. With the goal of expanding the application of CXCR4 theranostics to solid tumors, we aimed to elucidate the feasibility of CXCR4-targeted imaging in a variety of such neoplasms. Nineteen patients with newly diagnosed, treatment-naïve solid tumors including pancreatic adenocarcinoma or neuroendocrine tumor, cholangiocarcinoma, hepatocellular carcinoma, renal cell carcinoma, ovarian cancer, and prostate cancer underwent [Ga]Pentixafor PET/CT. CXCR4-mediated uptake was assessed both visually and semi-quantitatively by evaluation of maximum standardized uptake values (SUV) of both primary tumors and metastases. With physiologic liver uptake as reference, tumor-to-background ratios (TBR) were calculated. [Ga]Pentixafor findings were further compared to immunohistochemistry and [F]FDG PET/CT. On [Ga]Pentixafor PET/CT, 10/19 (52.6%) primary tumors were visually detectable with a median SUV of 5.4 (range, 1.7-16.0) and a median TBR of 2.6 (range, 0.8-7.4), respectively. The highest level of radiotracer uptake was identified in a patient with cholangiocarcinoma (SUV, 16.0; TBR, 7.4). The relatively low uptake on [Ga]Pentixafor was also noted in metastases, exhibiting a median SUV of 4.5 (range, 2.3-8.8; TBR, 1.7; range, 1.0-4.1). A good correlation between uptake on [Ga]Pentixafor and histological derived CXCR4 expression was noted ( = 0.62, < 0.05). In the 3 patients in whom [F]FDG PET/CT was available, [Ga]Pentixafor exhibited lower uptake in all lesions. In this cohort of newly diagnosed, treatment-naïve patients with solid malignancies, CXCR4 expression as detected by [Ga]Pentixafor-PET/CT and immunohistochemistry was rather moderate. Thus, CXCR4-directed imaging may not play a major role in the management of solid tumors in the majority of patients.
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http://dx.doi.org/10.3389/fonc.2019.00770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702266PMC
August 2019

Click Chemistry in the Design and Production of Hybrid Tracers.

ACS Omega 2019 Jul 22;4(7):12438-12448. Epub 2019 Jul 22.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands.

Hybrid tracers containing both fluorescent and radioactive imaging labels have demonstrated clinical potential during sentinel lymph node procedures. To combine these two labels on a single targeting vector that allows tumor-targeted imaging, end-labeling strategies are often applied. For αβ-integrin-targeting hybrid tracers, providing an excellent model for evaluating tracer development strategies, end-labeling-based synthesis provides a rather cumbersome synthesis strategy. Hence, the aim of this study was to investigate the use of heterobifunctional cyanine dyes in a click-chemistry-based synthesis strategy for RGD-based hybrid tracers. The triazole-based hybrid tracers and were obtained in fewer steps than and had partition coefficients of log  = -2.55 ± 0.10, -1.45 ± 0.03, and -2.67 ± 0.12, respectively. Both tracers were chemically stable, and the brightnesses of and were, respectively, 23 × 10 and 40 × 10 M cm; lower than that of the reference tracer (50 × 10 M cm). Assessment of serum protein binding revealed no statistically significant difference (44 ± 2 and 40 ± 2% bound for and , respectively; 36 ± 5% bound for ;  > 0.05). ( = 17.5 ± 6.0) had a statistically significantly higher affinity than the reference compound ( = 30.3 ± 5.7; < 0.0001), but had a statistically significantly lower affinity ( = 76.5 ± 18.3 nM; < 0.0001). Both and enabled in vivo visualization of the 4T1 tumor via fluorescence and single-photon emission computed tomography (SPECT) imaging. Biodistribution data (% ID/g) revealed a significant increase in nonspecific uptake in the kidney, liver, and muscle for both and . As a result of the higher background activity, the tumor-to-background ratio of the click-labeled RGD analogues was twofold lower compared to the end-labeled reference compound. The use of click chemistry labeling did not yield a pronounced negative effect on serum protein binding, in vitro stability, and receptor affinity; and tumors could still be visualized using SPECT and fluorescence imaging. However, quantitative in vivo biodistribution data suggest that the triazole and strained cyclooctyne moieties associated with this type of click chemistry negatively influence the pharmacokinetics of RGD peptides. Nevertheless, the design might still hold promise for other targets/targeting moieties.
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http://dx.doi.org/10.1021/acsomega.9b01484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682143PMC
July 2019

EANM procedure guidelines for radionuclide therapy with Lu-labelled PSMA-ligands (Lu-PSMA-RLT).

Eur J Nucl Med Mol Imaging 2019 Nov 22;46(12):2536-2544. Epub 2019 Aug 22.

Department of Nuclear Medicine, |Universitätsklinikum Essen, Essen, Germany.

Prostate-specific membrane antigen (PSMA) is expressed in most prostate cancers and can be identified by PSMA-ligand imaging, which has already become clinically accepted in several countries in- and outside Europe. PSMA-directed radioligand therapy (PSMA-RLT) with Lutetium-177 (Lu-PSMA) is currently undergoing clinical validation. Retrospective observational data have documented favourable safety and striking clinical responses. Recent results from a prospective clinical trial (phase II) have been published confirming high response rates, low toxicity and reduction of pain in metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed after conventional treatments. Such patients typically survive for periods less than 1.5 years. This has led some facilities to adopt compassionate or unproven use of this therapy, even in the absence of validation within a randomised-controlled trial. As a result, a consistent body of evidence exists to support efficacy and safety data of this treatment. The purpose of this guideline is to assist nuclear medicine specialists to deliver PSMA-RLT as an "unproven intervention in clinical practice", in accordance with the best currently available knowledge.
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http://dx.doi.org/10.1007/s00259-019-04485-3DOI Listing
November 2019

Validation of [I]CPCR4.3 as an investigative tool for the sensitive and specific detection of hCXCR4 and mCXCR4 expression in vitro and in vivo.

EJNMMI Res 2019 Aug 13;9(1):75. Epub 2019 Aug 13.

Chair for Pharmaceutical Radiochemistry, Technische Universität München, Walther-Meissner-Strasse 3, 85748, Garching, Germany.

Background: The development and clinical translation of [Ga] Pentixafor has substantially promoted the relevance of non-invasive PET imaging of CXCR4 expression in a broad spectrum of diseases, including cancer and inflammation. Its pronounced selectivity for the human receptor (hCXCR4), however, precludes the use of [Ga] Pentixafor for imaging receptor expression and dynamics in CXCR4-related diseases in endogenous mouse models. To overcome this restriction, [I]CPCR4.3, a structurally related pentapeptide ligand, has been evaluated as a preclinical tool for efficient in vitro and in vivo targeting of hCXCR4 and mCXCR4.

Results: Compared to the reference [Ga] Pentixafor, [I]CPCR4.3 showed 2.4- to 11-fold increased specific binding to human cancer cell lines with different hCXCR4 expression levels (Jurkat, Daudi, HT-29, SH-5YSY, MCF-7, LNCaP) as well as strong and highly specific binding to mCXCR4 expressing cells (mCXCR4-transfected CHO cells, Eμ-myc 1080, 4 T1), which was not detectable for [Ga]Pentixafor. This is the consequence of the equally high affinity of iodo-CPCR4 to hCXCR4 and mCXCR4 (IC = 5.4 ± 1.5 and 4.9 ± 1.7 nM, respectively) as opposed to [Ga] Pentixafor (hCXCR4: 42.4 ± 11.6 nM, mCXCR4: > 1000 nM). Additionally, [I]CPCR4.3 showed enhanced tracer internalization (factor of 1.5-2 compared to the reference). In vivo biodistribution studies in immunocompetent Black Six and immunocompromised CD-1 nude mice showed predominant hepatobiliary excretion of [I]CPCR4.3 (logP = 0.51), leading to high activity levels in liver and intestines. However, [I]CPCR4.3 also showed high and specific accumulation in organs with endogenous mCXCR4 expression (spleen, lung, adrenals), even at low receptor expression levels.

Conclusions: Due to its excellent hCXCR4 and mCXCR4 targeting efficiency, both in vitro and in vivo, [I]CPCR4.3 represents a sensitive and reliable tool for the species-independent quantification of CXCR4 expression. Its suboptimal clearance properties will certainly restrict its use for in vivo imaging applications using I (for SPECT) or I (for PET), but due to its high and specific accumulation in mCXCR4 expressing tissues, [I]CPCR4.3 holds promise as a powerful preclinical tool for the investigation and quantification of CXCR4 involvement and kinetics in various murine disease models via, e.g., biodistribution and autoradiography studies.
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http://dx.doi.org/10.1186/s13550-019-0545-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692420PMC
August 2019

Myocardial infarction triggers cardioprotective antigen-specific T helper cell responses.

J Clin Invest 2019 08 13;129(11):4922-4936. Epub 2019 Aug 13.

Department of Internal Medicine III, University Clinic Halle, Halle, Germany.

T cell autoreactivity is a hallmark of autoimmune diseases but can also benefit self-maintenance and foster tissue repair. Herein, we investigated whether heart-specific T cells exert salutary or detrimental effects in the context of myocardial infarction (MI), the leading cause of death worldwide. After screening more than 150 class-II-restricted epitopes, we found that myosin heavy chain alpha (MYHCA) was a dominant cardiac antigen triggering post-MI CD4+ T cell activation in mice. Transferred MYHCA614-629-specific CD4+ T (TCR-M) cells selectively accumulated in the myocardium and mediastinal lymph nodes (med-LN) of infarcted mice, acquired a Treg phenotype with a distinct pro-healing gene expression profile, and mediated cardioprotection. Myocardial Treg cells were also detected in autopsies from patients who suffered a MI. Noninvasive PET/CT imaging using a CXCR4 radioligand revealed enlarged med-LNs with increased cellularity in MI-patients. Notably, the med-LN alterations observed in MI patients correlated with the infarct size and cardiac function. Taken together, the results obtained in our study provide evidence showing that MI-context induces pro-healing T cell autoimmunity in mice and confirms the existence of an analogous heart/med-LN/T cell axis in MI patients.
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http://dx.doi.org/10.1172/JCI123859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819128PMC
August 2019