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

Abstract

Glioblastoma multiforme (GBM) is the most devastating primary brain tumour characterised by infiltrative growth and resistance to therapies. According to recent research, the sigma-1 receptor (sig1R), an endoplasmic reticulum chaperone protein, is involved in signaling pathways assumed to control the proliferation of cancer cells and thus could serve as candidate for molecular characterisation of GBM. To test this hypothesis, we used the clinically applied sig1R-ligand (S)-(−)-[18F]fluspidine in imaging studies in an orthotopic mouse model of GBM (U87-MG) as well as in human GBM tissue. A tumour-specific overexpression of sig1R in the U87-MG model was revealed in vitro by autoradiography. The binding parameters demonstrated target-selective binding according to identical KD values in the tumour area and the contralateral side, but a higher density of sig1R in the tumour. Different kinetic profiles were observed in both areas, with a slower washout in the tumour tissue compared to the contralateral side. The translational relevance of sig1R imaging in oncology is reflected by the autoradiographic detection of tumour-specific expression of sig1R in samples obtained from patients with glioblastoma. Thus, the herein presented data support further research on sig1R in neuro-oncology.

[18F]Fluspidine—A PET Tracer for Imaging of σ1 Receptors in the Central Nervous System

“…In a mouse model of glioblastoma multiforma, an increased σ 1 receptor density in the tumor was detected with ( S )-[ 18 F] 2 . An increased σ 1 receptor density was also observed during an autoradiographic analysis of samples from patients with glioblastoma using ( S )-[ 18 F] 2, confirming the translational relevance of σ 1 receptor imaging in oncology [ 59 ].…”

“… Fractions of unchanged PET tracer and radiometabolites in the plasma of various species determined at 30 and 60 min following intravenous administration of the corresponding radioligand [ 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ]. …”

Recent progress in nanomedicines for imaging and therapy of brain tumors

“…administration of (S)-(−)-[ 18 F]fluspidine in the U87-MG tumor-bearing mouse model revealed the distribution of (S)-(−)-[ 18 F]fluspidine at early times and later times. 99 In another example, in a U87 intracranial GBM mouse model, they developed an ultrasmall, renal-clearable gold nanocluster intrinsically radiolabeled with 64 Cu ( 64 Cu-AuNCs-FC131) for targeted PET imaging of CXCR4 and showed the effective delivery of 64 Cu-AuNCs-FC131 into the tumors. Furthermore, at various dosages, in vivo toxicity studies revealed specific binding to U87 cells with no significant safety concerns, showing its potential as a useful platform for GBM imaging and drug delivery (Fig.…”

“…MRI has low sensitivity but it provides the highest soft tissue contrast whereas CT provides low soft tissue contrast but it is fast compared to MRI. 99,104 PET has low spatial resolution but it is more sensitive compared to MRI. IR imaging has a very low depth of penetration but its sensitivity is high and it is fast.…”