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Theranostics 2020; 10(18):7938-7955. doi:10.7150/thno.47585 This issue Cite

Research Paper

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

François-Xavier Lepelletier^1,2*, Matthias Vandesquille^1,2*, Marie-Claude Asselin^2,3, Christian Prenant², Andrew C Robinson⁴, David M A Mann⁴, Michael Green^2,3, Elizabeth Barnett^2,3, Samuel D Banister⁵, Marco Mottinelli⁶, Christophe Mesangeau⁷, Christopher R McCurdy^6,8, Inga B Fricke^9*, Andreas H. Jacobs^9,10, Michael Kassiou⁵, Hervé Boutin^1,2✉

1. Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Neuroscience and Experimental Psychology, University of Manchester, Manchester, United Kingdom.
2. Wolfson Molecular Imaging Centre, University of Manchester, Manchester, United Kingdom.
3. Faculty of Biology, Medicine and Health, School of Health Sciences, Division of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, United Kingdom.
4. Salford Royal NHS Foundation Trust, Department of Clinical & Cognitive Neurosciences, Clinical Sciences Building, Salford, United Kingdom.
5. School of Chemistry, The University of Sydney, Sydney, Australia.
6. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA.
7. Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA.
8. UF Translational Drug Development Core, University of Florida, Gainesville, FL 32610, USA.
9. European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität (WWU), Münster, Germany.
10. Department of Geriatrics and Neurology, Johanniter Hospital, Bonn, Germany.
*Current addresses: FXL: Université de Caen Normandie, IUT Grand Ouest Normandie, Département Hygiène Sécurité Environnement, Rue des Noës Davy 14500 Vire-Normandie (E-mail: fx.lepelletier@gmail.com); MV: Institut Européen de Génomique du Diabète, 1 place de Verdun, 59045 Lille, France (E-mail: matthias.vandesquille@univ-lille.fr); IF: Bruker BioSpin MRI GmbH, Rudolf-Plank-Str. 23, 76275 Ettlingen, Germany (E-mail: inga.fricke@bruker.com).

✉ Corresponding author: Hervé Boutin, Wolfson Molecular Imaging Centre, University of Manchester, 27 Palatine Road, Manchester, M20 3LJ, UK; E-mail: herve.boutinac.uk; Phone: +44 161 275 0078.

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 (5HT_2B/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 5HT_2B/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.

Conclusion: This work shows that ¹⁸F-IAM6067 is a specific and selective S1R radiotracer. The absence or small changes in S1R detected here in animal models and human tissue warrants further investigations and suggests that S1R might not be the anticipated ideal biomarker for neuronal loss in neurodegenerative diseases such as AD and PD.

Keywords: Sigma 1 receptor, PET radiotracer, Parkinson's disease, Alzheimer's disease, animal model

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