Open AccessPreclinical Evaluation of [11C]YC-72-AB85 for In Vivo Visualization of Heat Shock Protein 90 in Brain and Cancer with Positron Emission Tomography
Author(s) -
Koen Vermeulen,
Romy Cools,
Emmanuelle Briard,
Yves P. Auberson,
Joseph Schoepfer,
Michel Koole,
Christopher Cawthorne,
Guy Bormans
Publication year - 2021
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/acschemneuro.1c00508
Subject(s) - in vivo , biodistribution , melanoma , positron emission tomography , heat shock protein , preclinical imaging , pathology , hsp90 inhibitor , ex vivo , in vitro , hsp90 , chemistry , cancer research , medicine , pharmacology , biology , nuclear medicine , biochemistry , microbiology and biotechnology , gene
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, [ 11 C]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 [ 11 C]YC-72-AB85 to tissue slices of mouse B16.F10 melanoma, PC3 prostate carcinoma, and rodent brain was evaluated using autoradiography. Biodistribution of [ 11 C]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 [ 11 C]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. [ 11 C]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.