Radiosynthesis and Evaluation of [18F]FEHSP990 as Novel PET Tracer for Hsp90 PET Imaging

Heat shock protein 90 (HSP90) is a critical chaperone in the protein quality control system, essential for maintaining cellular proteostasis. Aberrant HSP90 function has been implicated in Cancer and neurodegenerative disorders, making it an attractive therapeutic target and a potential biomarker for disease characterisation and progression using PET imaging. In this study, we aimed to develop the first fluorine-18 labelled brain permeable PET imaging agent, [¹⁸F]FEHSP990, suitable for imaging HSP90 in both brain and tumour tissue. The radiosynthesis of [¹⁸F]FEHSP990 was achieved with a radiochemical yield of 48 ± 29%, high radiochemical purity of > 99% and a molar activity of 213 ± 101 GBq/μmol at the end of synthesis. Competition binding studies in healthy mouse brain homogenate samples indicated a K_i value of approximately 200 nM. In vitro tracer binding to rodent brain and glioblastoma tumour tissue slices was high and deemed Hsp90-specific, as demonstrated by autoradiography blocking studies, whereas binding to living glioblastoma U87 cells was notably low. Ex vivo biodistribution and in vivo PET imaging studies in healthy rodents demonstrated limited brain exposure of the tracer, potentially due to insufficient affinity for HSP90 and/or restricted blood-brain barrier permeability. Further development of fluorine-18 labelled HSP90 tracers is warranted.

Hsp90; PET; brain; imaging; neurodegeneration; preclinical; tumour.