Radiochemistry and Preclinical PET Imaging of Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen
Radiotracers incorporating the urea-based Glu-NH-C(O)-NH-Lys group have gained prominence due to their role in targeting prostate-specific membrane antigen (PSMA)—a clinical biomarker of prostate cancer. Here, the synthesis, radiolabeling, and in vitro and in vivo characterization of two 68 Ga-radio...
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SAGE Publishing
2017-10-01
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| Series: | Molecular Imaging |
| Online Access: | https://doi.org/10.1177/1536012117737010 |
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| author | Eleni Gourni PhD Luigi Del Pozzo BSc Mark Bartholomä PhD Yvonne Kiefer BSc Philipp T. Meyer MD, PhD Helmut R. Maecke PhD Jason P. Holland D.Phil |
| author_facet | Eleni Gourni PhD Luigi Del Pozzo BSc Mark Bartholomä PhD Yvonne Kiefer BSc Philipp T. Meyer MD, PhD Helmut R. Maecke PhD Jason P. Holland D.Phil |
| author_sort | Eleni Gourni PhD |
| collection | DOAJ |
| description | Radiotracers incorporating the urea-based Glu-NH-C(O)-NH-Lys group have gained prominence due to their role in targeting prostate-specific membrane antigen (PSMA)—a clinical biomarker of prostate cancer. Here, the synthesis, radiolabeling, and in vitro and in vivo characterization of two 68 Ga-radiolabeled Glu-NH-C(O)-NH-Lys radiotracers conjugated to the desferrioxamine B (DFO) chelate were evaluated. Two linker groups based on amide bond and thiourea coupling chemistries were employed to develop 68 Ga-DFO-Nsucc-PSMA ( 68 Ga-4) and 68 Ga-DFO- p NCS-Bn-PSMA ( 68 Ga-7), respectively. Radiosynthesis proceeded quantitatively at room temperature with high radiochemical yields, chemical/radiochemical purities, and specific activities. Pharmacokinetic profiles of 68 Ga-4 and 68 Ga-7 were assessed using positron-emission tomography (PET) in mice bearing subcutaneous LNCaP tumors. Data were compared to the current clinical benchmark radiotracer 68 Ga-HBED-CC-PSMA ( 68 Ga-1) (HBED = N,N′-Bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N′-diacetic acid). Results indicated that the target binding affinity, protein association, blood pool and background organ clearance properties, and uptake in PSMA-positive lesions are strongly dependent on the nature of the chelate, the linker, and the spacer groups. Protein dissociation constants ( K d values) were found to be predictive of pharmacokinetics in vivo. Compared to 68 Ga-1, 68 Ga-4 and 68 Ga-7 resulted in decreased tumor uptake but enhanced blood pool clearance and reduced residence time in the kidney. The study highlights the importance of maximizing protein binding affinity during radiotracer optimization. |
| format | Article |
| id | doaj-art-80fc5fd6557c4066a3ee4da24b33cef8 |
| institution | Kabale University |
| issn | 1536-0121 |
| language | English |
| publishDate | 2017-10-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Molecular Imaging |
| spelling | doaj-art-80fc5fd6557c4066a3ee4da24b33cef82025-01-02T23:12:06ZengSAGE PublishingMolecular Imaging1536-01212017-10-011610.1177/1536012117737010Radiochemistry and Preclinical PET Imaging of Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane AntigenEleni Gourni PhD0Luigi Del Pozzo BSc1Mark Bartholomä PhD2Yvonne Kiefer BSc3Philipp T. Meyer MD, PhD4Helmut R. Maecke PhD5Jason P. Holland D.Phil6 German Cancer Research Center (DKFZ), Heidelberg, Germany German Cancer Research Center (DKFZ), Heidelberg, Germany Faculty of Medicine, Department of Nuclear Medicine, Medical Center—University of Freiburg, University of Freiburg, Freiburg, Germany Faculty of Medicine, Department of Nuclear Medicine, Medical Center—University of Freiburg, University of Freiburg, Freiburg, Germany Faculty of Medicine, Department of Nuclear Medicine, Medical Center—University of Freiburg, University of Freiburg, Freiburg, Germany Faculty of Medicine, Department of Nuclear Medicine, Medical Center—University of Freiburg, University of Freiburg, Freiburg, Germany Department of Chemistry, University of Zurich, Zurich, SwitzerlandRadiotracers incorporating the urea-based Glu-NH-C(O)-NH-Lys group have gained prominence due to their role in targeting prostate-specific membrane antigen (PSMA)—a clinical biomarker of prostate cancer. Here, the synthesis, radiolabeling, and in vitro and in vivo characterization of two 68 Ga-radiolabeled Glu-NH-C(O)-NH-Lys radiotracers conjugated to the desferrioxamine B (DFO) chelate were evaluated. Two linker groups based on amide bond and thiourea coupling chemistries were employed to develop 68 Ga-DFO-Nsucc-PSMA ( 68 Ga-4) and 68 Ga-DFO- p NCS-Bn-PSMA ( 68 Ga-7), respectively. Radiosynthesis proceeded quantitatively at room temperature with high radiochemical yields, chemical/radiochemical purities, and specific activities. Pharmacokinetic profiles of 68 Ga-4 and 68 Ga-7 were assessed using positron-emission tomography (PET) in mice bearing subcutaneous LNCaP tumors. Data were compared to the current clinical benchmark radiotracer 68 Ga-HBED-CC-PSMA ( 68 Ga-1) (HBED = N,N′-Bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N′-diacetic acid). Results indicated that the target binding affinity, protein association, blood pool and background organ clearance properties, and uptake in PSMA-positive lesions are strongly dependent on the nature of the chelate, the linker, and the spacer groups. Protein dissociation constants ( K d values) were found to be predictive of pharmacokinetics in vivo. Compared to 68 Ga-1, 68 Ga-4 and 68 Ga-7 resulted in decreased tumor uptake but enhanced blood pool clearance and reduced residence time in the kidney. The study highlights the importance of maximizing protein binding affinity during radiotracer optimization.https://doi.org/10.1177/1536012117737010 |
| spellingShingle | Eleni Gourni PhD Luigi Del Pozzo BSc Mark Bartholomä PhD Yvonne Kiefer BSc Philipp T. Meyer MD, PhD Helmut R. Maecke PhD Jason P. Holland D.Phil Radiochemistry and Preclinical PET Imaging of Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen Molecular Imaging |
| title | Radiochemistry and Preclinical PET Imaging of Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen |
| title_full | Radiochemistry and Preclinical PET Imaging of Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen |
| title_fullStr | Radiochemistry and Preclinical PET Imaging of Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen |
| title_full_unstemmed | Radiochemistry and Preclinical PET Imaging of Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen |
| title_short | Radiochemistry and Preclinical PET Imaging of Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen |
| title_sort | radiochemistry and preclinical pet imaging of ga desferrioxamine radiotracers targeting prostate specific membrane antigen |
| url | https://doi.org/10.1177/1536012117737010 |
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