PET of follicle-stimulating hormone receptor: Broadly applicable for imaging of cancer

Objectives Follicle-stimulating hormone receptor (FSHR) is a glycosylated transmembrane G-protein-coupled receptor. Mounting clinical evidence has demonstrated the selective over-expression of FSHR in the vasculature of a wide range of human cancers, which is closely associated with cancer metastasis. Our goal is to establish FSHR as a universal marker for imaging of cancer and develop a PET tracer for this purpose.

Methods A monoclonal antibody that binds to FSHR (FSHR-mAb) was conjugated to NOTA and labeled with ⁶⁴Cu. Flow cytometry and microscopy studies were performed in ovarian cancer cell lines with different FSHR expression level (high: CAOV-3; low: SKOV-3). PET imaging, biodistribution, histology examination, and RT-PCR were performed to evaluate the capability and specificity of ⁶⁴Cu-NOTA-FSHR-mAb for non-invasive PET imaging of FSHR in a variety of tumor models (ovarian cancer and others).

Results FACS analyses in FSHR-positive CAOV-3 cell line revealed similar FSHR binding affinity/specificity between FSHR-mAb and NOTA-FSHR-mAb, whereas both of them showed minimal non-specific binding to FSHR-negative SKOV-3 cells. ⁶⁴Cu-labeling was achieved with good yield and high specific activity. Serial PET imaging revealed that uptake of ⁶⁴Cu-NOTA-FSHR-mAb was 3.6±0.8, 13.2±0.6, and 14.6±1.2 %ID/g in the CAOV-3 tumor, and 2.3±1.2, 8.0±0.9, and 9.0±1.3 %ID/g in the SKOV-3 tumor at 4, 24, and 48 h post-injection respectively (n=3). ⁶⁴Cu-NOTA-FSHR-mAb also showed significant tumor-targeting capability in multiple other cancer types (e.g. prostate cancer and triple-negative breast cancer), demonstrating broad applicability of the tracer for PET imaging of cancer. Histology studies confirmed the universal expression pattern of FSHR in these cancer types (some on both tumor cells and vessels, some primarily vascular expression), as well as the in vivo FSHR specificity of ⁶⁴Cu-NOTA-FSHR-mAb.

Conclusions This is the first PET imaging study of FSHR expression. Prominent, persistent, and FSHR-specific uptake of ⁶⁴Cu-NOTA-FSHR-mAb was observed, which is generally applicable for multiple tumor types.