Evaluation of [11 C]NMS-E973 as a PET tracer for in vivo visualisation of HSP90

Theranostics
Koen VermeulenGuy Bormans

Abstract

Heat shock protein 90 is an ATP-dependent molecular chaperone important for folding, maturation and clearance of aberrantly expressed proteins and is abundantly expressed (1-2% of all proteins) in the cytosol of all normal cells. In some tumour cells, however, strong expression of HSP90 is also observed on the cell membrane and in the extracellular matrix and the affinity of tumoural HSP90 for ATP domain inhibitors was reported to increase over 100-fold compared to that of HSP90 in normal cells. Here, we explore [11C]NMS-E973 as a PET tracer for in vivo visualisation of HSP90 and as a potential tool for in vivo quantification of occupancy of HSP90 inhibitors. Methods: HSP90 expression was biochemically characterized in a panel of established cell lines including the melanoma line B16.F10. B16.F10 melanoma xenograft tumour tissue was compared to non-malignant mouse tissue. NMS-E973 was tested in vitro for HSP90 inhibitory activity in several tumour cell lines. HSP90-specific binding of [11C]NMS-E973 was evaluated in B16.F10 melanoma cells and B16.F10 melanoma, prostate cancer LNCaP and PC3, SKOV-3 xenograft tumour slices and in vivo in a B16.F10 melanoma mouse model. Results: Strong intracellular upregulation and abundant membra...Continue Reading

Citations

Oct 30, 2019·Apoptosis : an International Journal on Programmed Cell Death·Aleksandra Mielczarek-LewandowskaMalgorzata Czyz
Nov 23, 2020·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·P NordemanA Monazzam

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Methods Mentioned

BETA
xenograft
nuclear magnetic resonance
xenografts
ubiquitination

Clinical Trials Mentioned

NCT01393509
NCT01269593

Software Mentioned

IN Cell Developer
Graphpad
R
Compass IsotopePattern
Graphpad Prism
PMOD
studio
Optiquant

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