Radiolabeled (R)-(–)-5-iodo-3′-O-[2-(ε-guanidinohexanoyl)-2-phenylacetyl]-2′-deoxyuridine: A new theranostic for neuroblastoma

Zbigniew P. Kortylewicz, Don W. Coulter, Guang Han, Janina Baranowska-Kortylewicz

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Neuroblastoma, the most common extracranial solid tumor in children, accounts for nearly 8% of childhood cancers in the United States. It is a disease with pronounced clinical and biological heterogeneities. The amplification of MYCN, whose key tumorigenic functions include the promotion of proliferation, facilitation of the cell's entry into the S phase, and prevention of cells from leaving the cell cycle, correlates with poor prognosis. Patients with a high proliferation index disease have low survival rates. Neuroblastoma is one of the most radioresponsive of all human tumors. To exploit this radiosensitivity, radioactive guanidine (R)-(–)-5-[125I]iodo-3′-O-[2-(ε-guanidinohexanoyl)-2-phenylacetyl]-2′-deoxyuridine (9, GPAID) was designed. This compound enters neuroblastoma cells much like metaiodobenzylguanidine (MIBG). Additionally, it cotargets DNA of proliferating cells, an attribute especially advantageous in the treatment of MYCN-amplified tumors. GPAID was synthesized from the trimethylstannyl precursor with an average yield of >90% at the no-carrier-added specific activities. The norepinephrine transporter-aided delivery of GPAID to neuroblastoma cells was established in the competitive uptake studies with nonradioactive MIBG. The intracellular processing and DNA targeting properties were confirmed in the subcellular distribution experiments. Studies in a mouse model of neuroblastoma demonstrated the therapeutic potential of GPAID. The tin precursor of GPAID can be used to prepare compounds radiolabeled with single-photon emission computed tomography (SPECT)- and positron-emission tomography (PET)-compatible radionuclides. Accordingly, these reagents can function as theranostics useful in the individualized and comprehensive treatment strategies comprising treatment planning and the assessment of tumor responses as well as the targeted molecular radiotherapy employing treatment doses derived from the imaging data.

Original languageEnglish (US)
Pages (from-to)312-324
Number of pages13
JournalJournal of Labelled Compounds and Radiopharmaceuticals
Volume63
Issue number7
DOIs
StatePublished - Jun 15 2020

Keywords

  • Auger electron emitters
  • DNA targeted
  • MIBG
  • neuroblastoma
  • norepinephrine transporter
  • radioactive guanidines
  • theranostics

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Radiology Nuclear Medicine and imaging
  • Drug Discovery
  • Spectroscopy
  • Organic Chemistry

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