Radiolabeled 5-iodo-3′-O-(17β-succinyl-5α-androstan-3-one) -2′-deoxyuridine and its 5′-monophosphate for imaging and therapy of androgen receptor-positive cancers: Synthesis and biological evaluation

Zbigniew P. Kortylewicz, Jessica Nearman, Janina Baranowska-Kortylewicz

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

High levels of androgen receptor (AR) are often indicative of recurrent, advanced, or metastatic cancers. These conditions are also characterized by a high proliferative fraction. 5-Radioiodo-3′-O-(17β-succinyl-5α- androstan-3-one)-2′-deoxyuridine 8 and 5-radioiodo-3′-O-(17β- succinyl-5α-androstan-3-one)-2′-deoxyuridin-5′-yl monophosphate 13 target AR. They are also degraded intracellularly to 5-radioiodo-2′-deoxyuridine 1 and its monophosphate 20, respectively, which can participate in the DNA synthesis. Both drugs were prepared at the no-carrier-added level. Precursors and methods are readily adaptable to radiolabeling with various radiohalides suitable for SPECT and PET imaging, as well as endoradiotherapy. In vitro and in vivo studies confirm the AR-dependent interactions. Both drugs bind to sex hormone binding globulin. This binding significantly improves their stability in serum. Biodistribution and imaging studies show preferential uptake and retention of 8 and 13 in ip xenografts of human ovarian adenocarcinoma cells NIH:OVCAR-3, which overexpress AR. When these drugs are administered at therapeutic dose levels, a significant tumor growth arrest is observed.

Original languageEnglish (US)
Pages (from-to)5124-5143
Number of pages20
JournalJournal of Medicinal Chemistry
Volume52
Issue number16
DOIs
StatePublished - Aug 27 2009

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Androgen Receptors
Deoxyuridine
Neoplasms
Pharmaceutical Preparations
Sex Hormone-Binding Globulin
Therapeutics
Single-Photon Emission-Computed Tomography
Heterografts
Adenocarcinoma
androstan-3-one
2'-deoxyuridylic acid
DNA
Growth
Serum

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

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title = "Radiolabeled 5-iodo-3′-O-(17β-succinyl-5α-androstan-3-one) -2′-deoxyuridine and its 5′-monophosphate for imaging and therapy of androgen receptor-positive cancers: Synthesis and biological evaluation",
abstract = "High levels of androgen receptor (AR) are often indicative of recurrent, advanced, or metastatic cancers. These conditions are also characterized by a high proliferative fraction. 5-Radioiodo-3′-O-(17β-succinyl-5α- androstan-3-one)-2′-deoxyuridine 8 and 5-radioiodo-3′-O-(17β- succinyl-5α-androstan-3-one)-2′-deoxyuridin-5′-yl monophosphate 13 target AR. They are also degraded intracellularly to 5-radioiodo-2′-deoxyuridine 1 and its monophosphate 20, respectively, which can participate in the DNA synthesis. Both drugs were prepared at the no-carrier-added level. Precursors and methods are readily adaptable to radiolabeling with various radiohalides suitable for SPECT and PET imaging, as well as endoradiotherapy. In vitro and in vivo studies confirm the AR-dependent interactions. Both drugs bind to sex hormone binding globulin. This binding significantly improves their stability in serum. Biodistribution and imaging studies show preferential uptake and retention of 8 and 13 in ip xenografts of human ovarian adenocarcinoma cells NIH:OVCAR-3, which overexpress AR. When these drugs are administered at therapeutic dose levels, a significant tumor growth arrest is observed.",
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T1 - Radiolabeled 5-iodo-3′-O-(17β-succinyl-5α-androstan-3-one) -2′-deoxyuridine and its 5′-monophosphate for imaging and therapy of androgen receptor-positive cancers

T2 - Synthesis and biological evaluation

AU - Kortylewicz, Zbigniew P.

AU - Nearman, Jessica

AU - Baranowska-Kortylewicz, Janina

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N2 - High levels of androgen receptor (AR) are often indicative of recurrent, advanced, or metastatic cancers. These conditions are also characterized by a high proliferative fraction. 5-Radioiodo-3′-O-(17β-succinyl-5α- androstan-3-one)-2′-deoxyuridine 8 and 5-radioiodo-3′-O-(17β- succinyl-5α-androstan-3-one)-2′-deoxyuridin-5′-yl monophosphate 13 target AR. They are also degraded intracellularly to 5-radioiodo-2′-deoxyuridine 1 and its monophosphate 20, respectively, which can participate in the DNA synthesis. Both drugs were prepared at the no-carrier-added level. Precursors and methods are readily adaptable to radiolabeling with various radiohalides suitable for SPECT and PET imaging, as well as endoradiotherapy. In vitro and in vivo studies confirm the AR-dependent interactions. Both drugs bind to sex hormone binding globulin. This binding significantly improves their stability in serum. Biodistribution and imaging studies show preferential uptake and retention of 8 and 13 in ip xenografts of human ovarian adenocarcinoma cells NIH:OVCAR-3, which overexpress AR. When these drugs are administered at therapeutic dose levels, a significant tumor growth arrest is observed.

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