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

Abstract

Aberrant Hsp90 has been implied in cancer and neurodegenerative disorders. The development of a suitable Hsp90 Positron emission tomography (PET) probe can provide <i>in vivo</i> 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. <i>In vitro</i> 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. <i>In vivo</i> brain uptake was assessed by μPET studies in rats and a rhesus monkey. <i>In vitro</i> 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 <i>in vivo</i> 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.