Evaluation of 18F-IAM6067 as a sigma-1 receptor PET tracer for neurodegeneration in vivo in rodents and in human tissue

ABSTRACT

The sigma 1 receptor (S1R) is widely expressed in the CNS and is mainly located on the endoplasmic reticulum.
The S1R is involved in the regulation of many neurotransmission systems and, indirectly, in neurodegenerative
diseases. The S1R may therefore represent an interesting neuronal biomarker in neurodegenerative diseases
such as Parkinson’s (PD) or Alzheimer’s diseases (AD). Here we present the characterisation of the
S1R-specific 18F-labelled tracer 18F-IAM6067 in two animal models and in human brain tissue.
Methods: Wistar rats were used for PET-CT imaging (60 min dynamic acquisition) and metabolite analysis (1,
2, 5, 10, 20, 60 min post-injection). To verify in vivo selectivity, haloperidol, BD1047 (S1R ligand), CM398 (S2R
ligand) and SB206553 (5HT2B/C antagonist) were administrated for pre-saturation studies. Excitotoxic lesions
induced by intra-striatal injection of AMPA were also imaged by 18F-IAM6067 PET-CT to test the sensitivity of
the methods in a well-established model of neuronal loss. Tracer brain uptake was also verified by
autoradiography in rats and in a mouse model of PD (intrastriatal 6-hydroxydopamine (6-OHDA) unilateral
lesion). Finally, human cortical binding was investigated by autoradiography in three groups of subjects (control
subjects with Braak ≤2, and AD patients, Braak >2 & ≤4 and Braak >4 stages).
Results: We demonstrate that despite rapid peripheral metabolism of 18F-IAM6067, radiolabelled metabolites
were hardly detected in brain samples. Brain uptake of 18F-IAM6067 showed differences in S1R anatomical
distribution, namely from high to low uptake: pons-raphe, thalamus medio-dorsal, substantia nigra,
hypothalamus, cerebellum, cortical areas and striatum. Pre-saturation studies showed 79-90% blockade of the
binding in all areas of the brain indicated above except with the 5HT2B/C antagonist SB206553 and S2R ligand
CM398 which induced no significant blockade, indicating good specificity of 18F-IAM6067 for S1Rs. No
difference between ipsi- and contralateral sides of the brain in the mouse model of PD was detected. AMPA
lesion induced a significant 69% decrease in 18F-IAM6067 uptake in the globus pallidus matching the neuronal
loss as measured by NeuN, but only a trend to decrease (-16%) in the caudate putamen despite a significant 91%
decrease in neuronal count. Moreover, no difference in the human cortical binding was shown between AD
groups and controls.