First in vivo evaluation of the radiolabelled Hsp90 inhibitor [11C]onalespib for cancer and brain PET imaging
Year: 2026
Type: article
Abstract: Background : Heat shock protein 90 (Hsp90) is a key molecular chaperone involved in maintaining proteostasis, and its function and aberrant expression are linked to tumour progression and to neurodegeneration. Its overexpression in cancers and the clinical development of Hsp90 inhibitors, including the recently approved pimitespib (TAS-116, trade name Jeselhy®), highlights the need for non‑invasive imaging tools to assess Hsp90 expression. Current PET/SPECT tracers show limited performance. Onalespib, a clinically evaluated inhibitor with favourable chemical flexibility and identified as a promising radiosensitizer in glioblastoma, suggesting blood-brain barrier penetration, offers an attractive alternative. In this work, we report the first preclinical evaluation of [¹¹C]Onalespib to assess its suitability as an Hsp90‑targeted PET radiotracer for tumour and brain imaging. Results : [¹¹C]Onalespib was produced in high purity, with an appropriate radiochemical profile and a molar activity suitable for biological studies. In vitro autoradiography demonstrated strong Hsp90‑specific binding in U‑87 MG, MDA‑MB‑231, PC-3 tumour tissues and mouse brain sections, with the signal markedly reduced after preincubation with onalespib or the structurally unrelated inhibitor HSP990. Cell binding assays further confirmed saturable uptake in all three cancer cell lines, with substantial inhibition in the presence of onalespib and other Hsp90 inhibitors. Ex vivo biodistribution studies revealed pronounced abdominal activity and moderate uptake in U‑87 MG xenografts, whereas MDA‑MB‑231 tumours showed only minimal uptake, both with negligible brain signal under the same conditions. PET/CT imaging in both tumour models corroborated these findings and demonstrated effective in vivo blocking by HSP990 in U‑87 MG xenografts, together with limited penetration of [¹¹C]Onalespib into the brain. Plasma metabolite analysis in healthy mice indicated rapid metabolic degradation, with only a small fraction of intact tracer remaining at all measured time points, despite the good in vitro stability in phosphate buffer, mouse serum and human serum. Conclusions : [¹¹C]Onalespib was obtained with high purity and showed Hsp90-specific binding in tumour tissues, cells and brain tissue in vitro. In vivo PET/CT and biodistribution confirmed high abdominal accumulation, moderate tumour uptake and negligible brain penetration. Despite rapid metabolism, the tracer demonstrates clear Hsp90 specificity and requires further optimisation to develop a Hsp90-targeted radiotracers.
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,290
Awards: G3050989157, G3327512123, G3450116582, G3708031204, FB-III (“FB triple-I”) : Flanders BioImaging: Integrating Imaging Infrastructure from cell to man., G5695534749, Translational investigation of the role of Hsp90 in neurodegenerative proteinopathies using positron emission tomography (PET), A high-resolution and high-sensitivity hybrid small animal PET-CT system for combined molecular/functional and anatomical preclinical imaging in neurology, oncology and cardiology., Development of Hsp90 Isoform- Selective Inhibitors as a Novel Opioid Dose-Reduction Therapy, Engineering the Next Generation of Safer Hsp90 Inhibitors
OpenAlex ID: W7204544250