Vermeulen, Koen, Cools, Romy, Briard, Emmanuelle, Auberson, Yves, Schoepfer, Joseph, Koole, Michel, Cawthorne, Christopher and Bormans, Guy (2021) Preclinical evaluation of [11C]YC-72-AB85 for in vivo visualisation of heat shock protein 90 in brain and cancer with positron emission tomography. Molecular Pharmaceutics, 18 (9). pp. 3352-3364. ISSN 1543-83841543-8392

Abstract

Background and Purpose: Aberrant Hsp90 has been implied in cancer and neurodegenerative disorders. The development of a suitable Hsp90 PET probe can provide in vivo quantification of the expression levels of Hsp90 as a biomarker for diagnosis and follow up of cancer and 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 non-human primate.
Experimental Approach: 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.
Key Results: In vitro binding was deemed Hsp90 specific by blocking studies with Hsp90 inhibitors Onalespibonalespib and SNX-0723. Saturable Hsp90 binding was observed in tumour, blood and blood rich organs in mice. In combined pre-treatment 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.
Conclusion and Implications: [11C]YC-72-AB85 is a promising PET tracer for in vivo visualisation of Hsp90 in tumour and brain. Clear differences of Hsp90 binding to blood and blood-rich organs were observed in tumour 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.

Item Type:	Article
Keywords:	Hsp90, PET, B16.F10 melanoma, Brain, Non-human primate
Date Deposited:	14 Dec 2021 00:45
Last Modified:	14 Dec 2021 00:45
URI:	https://oak.novartis.com/id/eprint/44791