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  • 1
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    Synthesis and labeling of a squaric acid containing PSMA-inhibitor coupled to AAZTA5 for versatile labeling with 44Sc, 64Cu, 68Ga and 177Lu
    Elsevier BV ; 2020
    In:  Applied Radiation and Isotopes Vol. 156 ( 2020-02), p. 108867-
    Details
    In: Applied Radiation and Isotopes, Elsevier BV, Vol. 156 ( 2020-02), p. 108867-
    Type of Medium: Online Resource
    ISSN: 0969-8043
    URL: Article
    DOI: 10.1016/j.apradiso.2019.108867
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 1499873-7
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  • 2
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    Alpha-peptide receptor radionuclide therapy using actinium-225 labeled somatostatin receptor agonists and antagonists
    Frontiers Media SA ; 2022
    In:  Frontiers in Medicine Vol. 9 ( 2022-12-7)
    Details
    In: Frontiers in Medicine, Frontiers Media SA, Vol. 9 ( 2022-12-7)
    Abstract: Peptide receptor radionuclide therapy (PRRT) has over the last two decades emerged as a very promising approach to treat neuroendocrine tumors (NETs) with rapidly expanding clinical applications. By chelating a radiometal to a somatostatin receptor (SSTR) ligand, radiation can be delivered to cancer cells with high precision. Unlike conventional external beam radiotherapy, PRRT utilizes primarily β or α radiation derived from nuclear decay, which causes damage to cancer cells in the immediate proximity by irreversible direct or indirect ionization of the cells’ DNA, which induces apoptosis. In addition, to avoid damage to surrounding normal cells, PRRT privileges the use of radionuclides that have little penetrating and more energetic (and thus more ionizing) radiations. To date, the most frequently radioisotopes are β – emitters, particularly Yttrium-90 ( 90 Y) and Lutetium-177 ( 177 Lu), labeled SSTR agonists. Current development of SSTR-targeting is triggering the shift from using SSTR agonists to antagonists for PRRT. Furthermore, targeted α-particle therapy (TAT), has attracted special attention for the treatment of tumors and offers an improved therapeutic option for patients resistant to conventional treatments or even beta-irradiation treatment. Due to its short range and high linear energy transfer (LET), α-particles significantly damage the targeted cancer cells while causing minimal cytotoxicity toward surrounding normal tissue. Actinium-225 ( 225 Ac) has been developed into potent targeting drug constructs including somatostatin-receptor-based radiopharmaceuticals and is in early clinical use against multiple neuroendocrine tumor types. In this article, we give a review of preclinical and clinical applications of 225 Ac-PRRT in NETs, discuss the strengths and challenges of 225 Ac complexes being used in PRRT; and envision the prospect of 225 Ac-PRRT as a future alternative in the treatment of NETs.
    Type of Medium: Online Resource
    ISSN: 2296-858X
    URL: Article
    DOI: 10.3389/fmed.2022.1034315
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2775999-4
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  • 3
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    [68Ga]Ga-DATA5m-LM4, a PET Radiotracer in the Diagnosis of SST2R-Positive Tumors: Preclinical and First Clinical Results
    MDPI AG ; 2022
    In:  International Journal of Molecular Sciences Vol. 23, No. 23 ( 2022-11-23), p. 14590-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 23 ( 2022-11-23), p. 14590-
    Abstract: Radiolabeled somatostatin subtype 2 receptor (SST2R)-antagonists have shown advantageous profiles for cancer theranostics compared with agonists. On the other hand, the newly introduced hybrid chelator (6-pentanoic acid)-6-(amino)methyl-1,4-diazepinetriacetate (DATA5m) rapidly binds Ga-68 (t1/2: 67.7 min) at much lower temperature, thus allowing for quick access to “ready-for-injection” [68Ga]Ga-tracers in hospitals. We herein introduce [68Ga] Ga-DATA5m-LM4 for PET/CT imaging of SST2R-positive human tumors. LM4 was obtained by 4Pal3/Tyr3-substitution in the known SST2R antagonist LM3 (H-DPhe-c[DCys-Tyr-DAph(Cbm)-Lys-Thr-Cys]-DTyr-NH2) and DATA5m was coupled at the N-terminus for labeling with radiogallium (Ga-67/68). [67Ga] Ga-DATA5m-LM4 was evaluated in HEK293-SST2R cells and mice models in a head-to-head comparison with [67Ga]Ga-DOTA-LM3. Clinical grade [68Ga] Ga-DATA5m-LM4 was prepared and injected in a neuroendocrine tumor (NET) patient for PET/CT imaging. DATA5m-LM4 displayed high SST2R binding affinity. [67Ga]Ga-DATA5m-LM4 showed markedly higher uptake in HEK293-SST2R cells versus [67Ga] Ga-DOTA-LM3 and was stable in vivo. In HEK293-SST2R xenograft-bearing mice, it achieved longer tumor retention and less kidney uptake than [67Ga]Ga-DOTA-LM3. [68Ga] Ga-DATA5m-LM4 accurately visualized tumor lesions with high contrast on PET/CT. In short, [68Ga]Ga-DATA5m-LM4 has shown excellent prospects for the PET/CT diagnosis of SST2R-positive tumors, further highlighting the benefits of Ga-68 labeling in a hospital environment via the DATA5m-chelator route.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms232314590
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 4
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    Squaric Acid Bisphposphonates for Theranostics of Bone Metastasis – the Easy DOTA-Zoledronate
    Frontiers Media SA ; 2022
    In:  Frontiers in Nuclear Medicine Vol. 2 ( 2022-5-10)
    Details
    In: Frontiers in Nuclear Medicine, Frontiers Media SA, Vol. 2 ( 2022-5-10)
    Abstract: Bisphosponates are an interesting molecular class and in recent years their application has found its way into radiopharmaceutical research and thus into molecular imaging. In addition to great imaging of bone metastases, bisphospnate-based tracers for imaging also have some significant drawbacks. For example, their synthesis is often difficult. Additionally, this can lead to complex and almost impossible purification and quality control. This has limited the production and labeling of suitable molecular and their widespread use to a few facilities. Our squaric acid-based approach provides a way to overcome these problems and makes the synthesis as well as the purification of the compounds much easier. In addition, we were able to demonstrate that labeling with 68 Ga is possible under the typical conditions.
    Type of Medium: Online Resource
    ISSN: 2673-8880
    URL: Article
    DOI: 10.3389/fnume.2022.870910
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 3110523-3
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  • 5
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    Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach
    MDPI AG ; 2021
    In:  Molecules Vol. 26, No. 21 ( 2021-10-20), p. 6332-
    Details
    In: Molecules, MDPI AG, Vol. 26, No. 21 ( 2021-10-20), p. 6332-
    Abstract: (1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMA-expressing cancer diseases. Although there are several radiolabeled PSMA inhibitors available, the search for new compounds with improved pharmacokinetic properties and simplified synthesis is still ongoing. In this study, we developed PSMA ligands with two different hybrid chelators and a modified linker. Both compounds have displayed a promising pharmacokinetic profile. (2) Methods: DATA5m.SA.KuE and AAZTA5.SA.KuE were synthesized. DATA5m.SA.KuE was labeled with gallium-68 and radiochemical yields of various amounts of precursor at different temperatures were determined. Complex stability in phosphate-buffered saline (PBS) and human serum (HS) was examined at 37 °C. Binding affinity and internalization ratio were determined in in vitro assays using PSMA-positive LNCaP cells. Tumor accumulation and biodistribution were evaluated in vivo and ex vivo using an LNCaP Balb/c nude mouse model. All experiments were conducted with PSMA-11 as reference. (3) Results: DATA5m.SA.KuE was synthesized successfully. AAZTA5.SA.KuE was synthesized and labeled according to the literature. Radiolabeling of DATA5m.SA.KuE with gallium-68 was performed in ammonium acetate buffer (1 M, pH 5.5). High radiochemical yields ( 〉 98%) were obtained with 5 nmol at 70 °C, 15 nmol at 50 °C, and 60 nmol (50 µg) at room temperature. [68Ga]Ga-DATA5m.SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA5.SA.KuE and DATA5m.SA.KuE were in the nanomolar range. PSMA-specific internalization ratio was comparable to PSMA-11. In vivo and ex vivo studies of [177Lu] Lu-AAZTA5.SA.KuE, [44Sc]Sc-AAZTA5.SA.KuE and [68Ga] Ga-DATA5m.SA.KuE displayed specific accumulation in the tumor along with fast clearance and reduced off-target uptake. (4) Conclusions: Both KuE-conjugates showed promising properties especially in vivo allowing for translational theranostic use.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    URL: Article
    DOI: 10.3390/molecules26216332
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2008644-1
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  • 6
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    How deprotonation changes molecular self-assembly – an AFM study in liquid environment
    Royal Society of Chemistry (RSC) ; 2013
    In:  Soft Matter Vol. 9, No. 29 ( 2013), p. 7145-
    Details
    In: Soft Matter, Royal Society of Chemistry (RSC), Vol. 9, No. 29 ( 2013), p. 7145-
    Type of Medium: Online Resource
    ISSN: 1744-683X , 1744-6848
    URL: Article
    DOI: 10.1039/c3sm50262g
    Language: English
    Publisher: Royal Society of Chemistry (RSC)
    Publication Date: 2013
    detail.hit.zdb_id: 2191476-X
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  • 7
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    From Automated Synthesis to In Vivo Application in Multiple Types of Cancer—Clinical Results with [68Ga]Ga-DATA5m.SA.FAPi
    MDPI AG ; 2022
    In:  Pharmaceuticals Vol. 15, No. 8 ( 2022-08-14), p. 1000-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 15, No. 8 ( 2022-08-14), p. 1000-
    Abstract: Radiolabeled FAPI (fibroblast activation protein inhibitors) recently gained attention as widely applicable imaging and potential therapeutic compounds targeting CAF (cancer-associated fibroblasts) or DAF (disease-associated fibroblasts in benign disorders). Moreover, the use of FAPI has distinct advantages compared to FDG (e.g., increased sensitivity in regions with high glucose metabolism, no need for fasting, and rapid imaging). In this study, we wanted to evaluate the radiochemical synthesis and the clinical properties of the new CAF-targeting tracer [68Ga]Ga-DATA5m.SA.FAPi. The compound consists of a (radio)chemically easy to use hybrid chelate DATA.SA, which can be labeled at low temperatures, making it an interesting molecule for ‘instant kit-type’ labeling, and a squaric acid moiety that provides distinct advantages for synthesis and radiolabeling. Our work demonstrates that automatic synthesis of the FAP inhibitor [68Ga] Ga-DATA5m.SA.FAPi is feasible and reproducible, providing convenient access to this new hybrid chelator-based tracer. Our studies demonstrated the diagnostic usability of [68Ga]Ga-DATA5m.SA.FAPi for the unambiguous detection of cancer-associated fibroblasts of various carcinomas and their metastases (NSCLC, liposarcoma, parotid tumors, prostate cancer, and pancreas adenocarcinoma), while physiological uptake in brain, liver, intestine, bone, and lungs was very low.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph15081000
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2193542-7
    SSG: 15,3
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  • 8
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    Mild and efficient 64 Cu labeling of perhydro-1, 4-diazepine derivatives for potential use with large peptides, proteins and antibodies
    Walter de Gruyter GmbH ; 2020
    In:  Radiochimica Acta Vol. 108, No. 7 ( 2020-07-28), p. 555-563
    Details
    In: Radiochimica Acta, Walter de Gruyter GmbH, Vol. 108, No. 7 ( 2020-07-28), p. 555-563
    Abstract: DATA (6-Amino-1,4-diazapine-triacetate) and AAZTA (6-Amino-1,4-diazapine-tetracetate) chelators represent a novel approach representing hybrid-chelates: possessing significant cyclic and acyclic character. It is believed that flexibility of the acyclic part facilitates rapid complexation, whilst the preorganized cyclic part minimizes the energy barrier to complexation and inhibits decomplexation processes. So far, these chelators have been used exclusively with 44 Sc and 68 Ga only. Recent results with nat Cu predict high stabilities for Cu-AAZTA, yet no radioactive labeling of AAZTA or DATA with 64 Cu or any additional radioactive isotope has been reported. We present the one pot synthesis of the bifunctional derivatives AAZTA 5 OMe and DATA 5m OMe and their labeling with 64 Cu. In addition, in vitro stability of the respective complexes are presented.
    Type of Medium: Online Resource
    ISSN: 2193-3405 , 0033-8230
    URL: Article
    DOI: 10.1515/ract-2019-3167
    Language: English
    Publisher: Walter de Gruyter GmbH
    Publication Date: 2020
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  • 9
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    Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA5m chelators
    Springer Science and Business Media LLC ; 2020
    In:  EJNMMI Radiopharmacy and Chemistry Vol. 5, No. 1 ( 2020-12)
    Details
    In: EJNMMI Radiopharmacy and Chemistry, Springer Science and Business Media LLC, Vol. 5, No. 1 ( 2020-12)
    Abstract: Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelator-linker systems. Here, we report squaric acid (SA) containing bifunctional DATA 5m and DOTA chelators based on UAMC1110 as pharmacophor. The novel radiopharmaceuticals DOTA.SA.FAPi and DATA 5m .SA.FAPi with their non-radioactive derivatives were characterized for in vitro inhibitory efficiency to FAP and PREP, respectively and radiochemical investigated with gallium-68. Further, first proof-of-concept in vivo animal study followed by ex vivo biodistribution were determined with [ 68 Ga]Ga-DOTA.SA.FAPi. Results [ 68 Ga]Ga-DOTA.SA.FAPi and [ 68 Ga]Ga-DATA 5m .SA.FAPi showed high complexation 〉  97% radiochemical yields after already 10 min and high stability over a period of 2 h. Affinity to FAP of DOTA.SA.FAPi and DATA 5m .SA.FAPi and its nat Ga and nat Lu-labeled derivatives were excellent resulting in low nanomolar IC 50 values of 0.7–1.4 nM. Additionally, all five compounds showed low affinity for the related protease PREP (high IC 50 with 1.7–8.7 μM). First proof-of-principle in vivo PET-imaging animal studies of the [ 68 Ga]Ga-DOTA.SA.FAPi precursor in a HT-29 human colorectal cancer xenograft mouse model indicated promising re sults with high accumulation in tumor (SUV mean of 0.75) and low background signal. Ex vivo biodistribution showed highest uptake in tumor (5.2%ID/g) at 60 min post injection with overall low uptake in healthy tissues. Conclusion In this work, novel PET radiotracers targeting fibroblast activation protein were synthesized and biochemically investigated. Critical substructures of the novel compounds are a squaramide linker unit derived from the basic motif of squaric acid, DOTA and DATA 5m bifunctional chelators and a FAP-targeting moiety. In conclusion, these new FAP-ligands appear promising, both for further research and development as well as for first human application.
    Type of Medium: Online Resource
    ISSN: 2365-421X
    URL: Article
    DOI: 10.1186/s41181-020-00102-z
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2843088-8
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  • 10
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    Squaric Acid-Based Radiopharmaceuticals for Tumor Imaging and Therapy
    American Chemical Society (ACS) ; 2021
    In:  Bioconjugate Chemistry Vol. 32, No. 7 ( 2021-07-21), p. 1223-1231
    Details
    In: Bioconjugate Chemistry, American Chemical Society (ACS), Vol. 32, No. 7 ( 2021-07-21), p. 1223-1231
    Type of Medium: Online Resource
    ISSN: 1043-1802 , 1520-4812
    URL: Article
    URL: Article
    DOI: 10.1021/acs.bioconjchem.1c00305
    DOI: 10.1021/acs.bioconjchem.1c00305.s001
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2021
    detail.hit.zdb_id: 1500067-9
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