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Radiochemistry and Preclinical PET Imaging of 68Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen


Gourni, Eleni; et al; Holland, Jason P (2017). Radiochemistry and Preclinical PET Imaging of 68Ga-Desferrioxamine Radiotracers Targeting Prostate-Specific Membrane Antigen. Molecular Imaging, 16:1-11.

Abstract

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 68Ga-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 68Ga-DFO-Nsucc-PSMA (68Ga-4) and 68Ga-DFO-pNCS-Bn-PSMA (68Ga-7), respectively. Radiosynthesis proceeded quantitatively at room temperature with high radiochemical yields, chemical/radiochemical purities, and specific activities. Pharmacokinetic profiles of 68Ga-4 and 68Ga-7 were assessed using positron-emission tomography (PET) in mice bearing subcutaneous LNCaP tumors. Data were compared to the current clinical benchmark radiotracer 68Ga-HBED-CC-PSMA (68Ga-1) (HBED ¼ N,N0-Bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N0-diacetic acid). Results indicated that the target binding affinity, protein association, blood pool and background organ clearance properties, and uptake in PSMApositive lesions are strongly dependent on the nature of the chelate, the linker, and the spacer groups. Protein dissociation constants (Kd values) were found to be predictive of pharmacokinetics in vivo. Compared to 68Ga-1, 68Ga-4 and 68Ga-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.

Abstract

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 68Ga-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 68Ga-DFO-Nsucc-PSMA (68Ga-4) and 68Ga-DFO-pNCS-Bn-PSMA (68Ga-7), respectively. Radiosynthesis proceeded quantitatively at room temperature with high radiochemical yields, chemical/radiochemical purities, and specific activities. Pharmacokinetic profiles of 68Ga-4 and 68Ga-7 were assessed using positron-emission tomography (PET) in mice bearing subcutaneous LNCaP tumors. Data were compared to the current clinical benchmark radiotracer 68Ga-HBED-CC-PSMA (68Ga-1) (HBED ¼ N,N0-Bis(2-hydroxy-5-(ethylene-beta-carboxy)benzyl)ethylenediamine N,N0-diacetic acid). Results indicated that the target binding affinity, protein association, blood pool and background organ clearance properties, and uptake in PSMApositive lesions are strongly dependent on the nature of the chelate, the linker, and the spacer groups. Protein dissociation constants (Kd values) were found to be predictive of pharmacokinetics in vivo. Compared to 68Ga-1, 68Ga-4 and 68Ga-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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2017
Deposited On:08 Feb 2018 11:25
Last Modified:18 Apr 2018 11:49
Publisher:BC Decker
ISSN:1535-3508
Funders:SNSF Professorship PP00P2_163683, ERC-StG-2015, NanoSCAN – 676904
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1177/1536012117737010
Project Information:
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSNSF Professorship PP00P2_163683
  • : Funder
  • : Grant ID
  • : Project TitleERC-StG-2015, NanoSCAN – 676904

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