Bridging from Brain to Tumor Imaging: (S)-(−)- and (R)-(+)-[18F]Fluspidine for Investigation of Sigma-1 Receptors in Tumor-Bearing Mice

Abstract

Sigma-1 receptors (Sig1R) are highly expressed in various human cancer cells and hence imaging of this target with positron emission tomography (PET) can contribute to a better understanding of tumor pathophysiology and support the development of antineoplastic drugs. Two Sig1R-specific radiolabeled enantiomers (S)-(−)- and (R)-(+)-[18F]fluspidine were investigated in several tumor cell lines including melanoma, squamous cell/epidermoid carcinoma, prostate carcinoma, and glioblastoma. Dynamic PET scans were performed in mice to investigate the suitability of both radiotracers for tumor imaging. The Sig1R expression in the respective tumors was confirmed by Western blot. Rather low radiotracer uptake was found in heterotopically (subcutaneously) implanted tumors. Therefore, a brain tumor model (U87-MG) with orthotopic implantation was chosen to investigate the suitability of the two Sig1R radiotracers for brain tumor imaging. High tumor uptake as well as a favorable tumor-to-background ratio was found. These results suggest that Sig1R PET imaging of brain tumors with [18F]fluspidine could be possible. Further studies with this tumor model will be performed to confirm specific binding and the integrity of the blood-brain barrier (BBB).

In vitroandin vivosigma 1 receptor imaging studies in different disease states

“…[184][185][186] σ1Rs are highly expressed in different types of tumors and several peer-reviewed studies show the therapeutic and diagnostic potential of σ1R ligands in cancer. 154,[187][188][189] Therefore, σ1R targeted radionuclide therapies are considered to be radiotheranostics. 186 The imaging, or diagnostic component, identifies the extent of sigma receptor expression in the tumor.…”

Approaches to PET Imaging of Glioblastoma

“…For example, [ 18 was also found to be irreversible and not suitable for neuroimaging [75]. Recently, [ 18 F](S)-Fluspidine ( 18) [76] was developed and evaluated in human [77]. The pharmacokinetics are improved, and with xenograft mouse models of glioblastoma have visible increases in radioligand binding.…”

Sigma-1 Receptor Positron Emission Tomography: A New Molecular Imaging Approach Using (S)-(−)-[18F]Fluspidine in Glioblastoma

“…Molecules 2020, 25, x FOR PEER REVIEW 3 of 17 using heterotopic brain tumour models, as by the group of van Waarde, or orthotopic models, as by our group [39,40]. Encouraged by the approval of the in-house developed radiopharmaceutical (S)-(−)-[ 18 F]fluspidine for clinical trials (EudraCT Numbers: 2014-005427-27, 2016-001757-41), the promising results of a collaborative pilot study in an orthotopic mouse model of GBM [40], and the establishment of orthotopic brain tumour models in our group, we decided to investigate further the relevance of sig1R in brain cancer biology and to evaluate the potential of (S)-(−)-[ 18 F]fluspidine-PET to characterise brain tumours on a molecular level. We report herein on the assessment of GBM-specific expression of sig1R by a combination of in vitro and in vivo approaches using mice bearing intracranial U87-MG tumours as a preclinical orthotopic model of human GBM and the sig1R-specific radioligand (S)-(−)-[ 18 F]fluspidine.…”

“…Already different radiotracers have been developed to investigate the expression of sig1R by PET such as [ 18 F]FMSA4503 [36], [ 18 F]SFE or [ 18 F]FTC-146 [37,38]. However, only [ 11 C]SA4503 and (S)-(−)-[ 18 F]fluspidine were applied in research on the in vivo imaging of sig1R in brain tumours using heterotopic brain tumour models, as by the group of van Waarde, or orthotopic models, as by our group [39,40].…”