Preclinical Evaluation of [ 11 C]YC-72-AB85 for In Vivo Visualization of Heat Shock Protein 90 in Brain and Cancer with Positron Emission Tomography

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Authors

  • Koen Vermeulen
  • Romy Cools
  • Emmanuelle Briard
  • Yves Auberson
  • Joseph Schoepfer
  • Michel Koole
  • Christopher Cawthorne
  • Guy Bormans

Institutes & Expert groups

  • KUL - Katholieke Universiteit Leuven
  • NIBR - Novartis Institutes for BioMedical Research

Documents & links

Abstract

Aberrant Hsp90 has been implied in cancer and neurodegenerative disorders. The development of a suitable Hsp90 Positron emission tomography (PET) probe can provide in vivo quantification of the expression levels of Hsp90 as a biomarker for diagnosis and follow-up of cancer and central nervous system (CNS) disease progression. In this respect, [11C]YC-72-AB85 was evaluated as an Hsp90 PET probe in B16.F10 melanoma bearing mice and its brain uptake was determined in rats and nonhuman primate. In vitro binding of [11C]YC-72-AB85 to tissue slices of mouse B16.F10 melanoma, PC3 prostate carcinoma, and rodent brain was evaluated using autoradiography. Biodistribution of [11C]YC-72-AB85 was evaluated in healthy and B16.F10 melanoma mice. In vivo brain uptake was assessed by μPET studies in rats and a rhesus monkey. In vitro binding was deemed Hsp90-specific by blocking studies with heterologous Hsp90 inhibitors onalespib and SNX-0723. Saturable Hsp90 binding was observed in brain, tumor, blood, and blood-rich organs in mice. In combined pretreatment and displacement studies, reversible and Hsp90-specific binding of [11C]YC-72-AB85 was observed in rat brain. Dynamic μPET brain scans in baseline and blocking conditions in a rhesus monkey indicated Hsp90-specific binding. [11C]YC-72-AB85 is a promising PET tracer for in vivo visualization of Hsp90 in tumor and brain. Clear differences of Hsp90 binding to blood and blood-rich organs were observed in tumor vs control mice. Further, we clearly demonstrate, for the first time, binding to a saturable Hsp90 pool in brain of rats and a rhesus monkey.

Details

Original languageEnglish
Article number1c00508
Pages (from-to)3915-3927
Number of pages13
JournalACS Chemical Neuroscience
Volume12
Issue number20
DOIs
Publication statusPublished - 20 Oct 2021

Keywords

  • Hsp90, PET, Brain, Neurodegenerative disorders, Nonhuman primate, B16.F10 melanoma

ID: 7411006