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Photoradiosynthesis of 68Ga-Labeled HBED-CC-Azepin-MetMAb for Immuno-PET of c-MET Receptors


Fay, Rachael; Gut, Melanie; Holland, Jason P (2019). Photoradiosynthesis of 68Ga-Labeled HBED-CC-Azepin-MetMAb for Immuno-PET of c-MET Receptors. Bioconjugate Chemistry, 30(6):1814-1820.

Abstract

In an alternative approach for radiotracer design, a photoactivatable HBED-CC-PEG3-ArN3 chelate was synthesized and photoconjugated to the anti-c-MET antibody MetMAb (onartuzumab). Photoconjugation gave the functionalized protein HBED-CC-azepin-MetMAb with a photochemical conversion of 18.5 ± 0.5% (n = 2) which was then radiolabeled with 68Ga3+ ions. The purified and formulated [68Ga]GaHBED-CC-azepin-MetMAb radiotracer was evaluated in vitro and in vivo. Standard stability tests and cellular binding assays confirmed that the radiotracer remained radiochemically pure and immunoreactive after photochemical conjugation. [68Ga]GaHBED-CC-azepin-MetMAb showed specific uptake in c-MET-positive MKN-45 (high-expression) and PC-3 (low/moderate expression) tumors with tumor-associated activities at 6 h post-administration of 10.33 ± 1.27 (n = 5) and 3.88 ± 1.27 (n = 3) %ID/g, respectively. In competitive blocking experiments, MKN-45 tumor uptake was reduced by approximately 55% (P-value <0.001 compared with nonblocked experiments) confirming specific radiotracer binding to c-MET in vivo. Radiochemical, cellular, and in vivo experiments confirmed that the photoradiochemical approach is a viable tool to synthesize new radiotracers for immuno-PET.

Abstract

In an alternative approach for radiotracer design, a photoactivatable HBED-CC-PEG3-ArN3 chelate was synthesized and photoconjugated to the anti-c-MET antibody MetMAb (onartuzumab). Photoconjugation gave the functionalized protein HBED-CC-azepin-MetMAb with a photochemical conversion of 18.5 ± 0.5% (n = 2) which was then radiolabeled with 68Ga3+ ions. The purified and formulated [68Ga]GaHBED-CC-azepin-MetMAb radiotracer was evaluated in vitro and in vivo. Standard stability tests and cellular binding assays confirmed that the radiotracer remained radiochemically pure and immunoreactive after photochemical conjugation. [68Ga]GaHBED-CC-azepin-MetMAb showed specific uptake in c-MET-positive MKN-45 (high-expression) and PC-3 (low/moderate expression) tumors with tumor-associated activities at 6 h post-administration of 10.33 ± 1.27 (n = 5) and 3.88 ± 1.27 (n = 3) %ID/g, respectively. In competitive blocking experiments, MKN-45 tumor uptake was reduced by approximately 55% (P-value <0.001 compared with nonblocked experiments) confirming specific radiotracer binding to c-MET in vivo. Radiochemical, cellular, and in vivo experiments confirmed that the photoradiochemical approach is a viable tool to synthesize new radiotracers for immuno-PET.

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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
Scopus Subject Areas:Life Sciences > Biotechnology
Physical Sciences > Bioengineering
Physical Sciences > Biomedical Engineering
Life Sciences > Pharmacology
Life Sciences > Pharmaceutical Science
Physical Sciences > Organic Chemistry
Language:English
Date:19 June 2019
Deposited On:07 Feb 2020 15:23
Last Modified:29 Jul 2020 14:00
Publisher:American Chemical Society (ACS)
ISSN:1043-1802
OA Status:Green
Publisher DOI:https://doi.org/10.1021/acs.bioconjchem.9b00342
Project Information:
  • : FunderSNSF
  • : Grant IDPP00P2_163683
  • : Project TitleAdvanced radiochemical methods for multi-modal imaging with nanomedicines
  • : FunderH2020
  • : Grant ID676904
  • : Project TitleNanoSCAN - Developing multi-modality nanomedicines for targeted annotation of oncogenic signaling pathways
  • : FunderKrebsliga
  • : Grant IDKLS-4257-08-2017
  • : Project Title

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