Development of Radiotracers for Imaging of Sigma1-Receptors in the Human Brain
Medical Physics, Biomedical Technology
Nuclear Medicine, Radiotherapy, Radiobiology
Final Report Abstract
The Sigma 1 receptor is a chaperone protein localized at the endoplasmic reticulum (ER) that can translocate under ER stress, a mechanism which is part of the pathophysiology of MDD. The aim of this first-in-man PET study was to assess quantitatively the cerebral Sigma 1 receptor availability in vivo in patients with MDD and to compare it with healthy controls (HC) using the recently developed radioligand (S)-(-)-[18F]fluspidine and PET. In this study, we successfully quantified for the first time the Sigma 1 receptor availability in vivo in patients with acute MDD (ICD-10: depressive disorder) without anti-depressive drug therapy. In this study, in acute unmedicated MDD, compared with HC, we demonstrated higher Sigma 1 receptor binding within cortico-striato-(para)limbic brain regions (+15% to +25%), which are typically involved in the pathophysiology of MDD. In an acute toxicity study in rats, (-)-fluspidine did not cause any toxicological changes in tissues and the no observed effect level (NOEL) was determined to be 620 microgram/kg (highest tested dose). Further safety, metabolism and tolerability analyses revealed that (S)-(-)[18F]fluspidine is a safe, adequately and metabolically stable, as well as highly tolerable PET ligand. The effective dose (ED) of (S)-(-)[18F]fluspidine was calculated as 21.0 micro Sv/MBq, which confirms that the radiation dose from (S)-(-)[18F]fluspidine imaging is within acceptable limits. Determination of distribution volumes (VT) by (S)-(-)[18F]fluspidine PET and kinetic modeling is feasible and robust. VT can be estimated within all cortical regions with a 1TCM or 2TCM model from 90 min TACs. Short measurement times and high VT make (S)-(-)[18F]fluspidine well suited for quantification of the Sigma 1 receptor availability and respective changes in neuropsychiatric diseases. Compared with patients with MDD-negative for a family history of depression [MDD(-)], in patients with MDD-positive for a family history of depression [MDD(+)], the Sigma 1 receptor availability was significantly higher within frontal and cingulate cortices and hippocampus, suggesting that there are distinct genetic subtypes of MDD and that the major depressive episode (MDE) in MDD(+) is more severe as compared to MDD(-). There is a positive association between striatal-insular-cinculate and thalamic Sigma 1 receptor availability and the severity of acute depressive symptoms as assessed by the the Hamilton Depression Scale (HAMD) in MDD. Of note, there is a negative relationship between the number of depressive episodes or duration of MD, measures of chronic stage and severity of MDD, and the Sigma 1 receptor availability, especially within the orbitofrontal cortex and hypothalamus. Thus, increased Sigma 1 receptor availability in the acute MDE of MDD and a positive association between Sigma 1 receptor availability and the severity of acute depressive symptoms of MDD is suggested to reflect neuroadaptive upregulation of Sigma 1 receptors counteracting ER stress. The negative relationship found in this study between Sigma 1 receptor binding and the number of depressive episodes or duration of MDD may be caused by exhaustion of compensatory Sigma 1 receptor-related mechanisms leading to apoptosis and neuroprogressive degeneration in the severest, late stages of MDD. Therefore, this PET study supports the hypothesis, as suggested by preclinical Sigma 1 receptor-knock-out mice studies and clinical studies using anti-depressive drugs, that Sigma 1 receptors are critically involved in the pathophysiology of MDD. Our PET findings are fostered by the fact that patients with MDD enrolled in this sigma1 receptor PET study were acutely depressed and without anti-depressive drugs to exclude effects of ongoing drug therapy. Of note, we furthermore showed that the Sigma 1 receptor availability is significantly higher in MDD with a positive family history of depression, as compared with MDD without a family history of depression. Future PET studies to investigate the Sigma 1 receptor availability in MDD with acute MDE and in remission before and following anti-depressive drug therapy and in healthy subjects at high risk of MDD are required to gain more insight into the Sigma 1 receptor pathophysiology and its impact for MDD and may pave the way towards the development of personalized medicinal treatment of patients with MDD.
Publications
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Synthesis, characterization, and metabolism studies of fluspidine enantiomers. ChemMedChem. 2013, 8, 2047-2056
Holl K, Falck E, Köhler J, Schepmann D, Humpf HU, Brust P, Wünsch B
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Asymmetric synthesis of spirocyclic 2-benzopyrans for positron emission tomography of σ1 receptors in the brain. Pharmaceuticals 2014, 7, 78 - 112
Holl K, Schepmann D, Fischer S, Ludwig FA, Hiller A, Donat CK, Deuther-Conrad W, Brust P, Wünsch B
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Automation of the radiosynthesis and purification procedures for [18F]fluspidine preparation, a new radiotracer for clinical investigations in PET imaging of σ1 receptors in brain. Appl Radiat Isot. 2014; 84:1-7
Maisonial-Besset A, Funke U, Wenzel B, Fischer S, Holl K, Wünsch B, Steinbach J, Brust P
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Distinctive in vivo kinetics of the new sigma1 receptor ligands (R)-(+) and (S)-(-)-18F-Fluspidine in porcine brain. J Nucl Med. 2014; 55:1730-1736
Brust P, Deuther-Conrad W, Becker G, Patt M, Donat CK, Sittsworth S, Fischer S, Hiller A, Wenzel B, Dukic-Stefanovic S, Hesse S, Steinbach J, Wünsch B, Lever S, Sabri O
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Sharpless asymmetric dihydroxylation as key step in the enantioselective synthesis of spirocyclic σ1 receptor ligands. Tetrahedron: Asymmetry 2014, 25, 268-277
Holl K, Schepmann D, Daniliuc CG, Wünsch B
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Comparison of in silico, electrochemical, in vitro and in vivo metabolism of a homologous series of (radio)fluorinated σ1 receptor ligands designed for positron emission tomography. ChemMedChem. 2016; 11:1-15
Wiese C, Große Maestrup E, Galla F, Schepmann D, Hiller A, Fischer S, Ludwig FA, Deuther-Conrad W, Donat CK, Brust P, Büter L, Karst U, Wünsch B
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Evaluation of the enantiomer specific biokinetics and radiation doses of [18F]Fluspidine - a new tracer in clinical translation for imaging of σ₁ receptors. Molecules. 2016; 21:pii: E1164
Kranz M, Sattler B, Wüst N, Deuther-Conrad W, Patt M, Meyer PM, Fischer S, Donat CK, Wünsch B, Hesse S, Steinbach J, Brust P, Sabri O
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First-inman incorporation dosimetry of (S)-(–)-[18F]fluspidine. J. Nucl. Med. 2016; 57:10P
Sattler B, Kranz M, Wuest N, Patt M, Meyer P, Deuther-Conrad W, Fischer S, Wünsch B, Brust P, Sabri O
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PET imaging evaluation of four sigma1 radiotracers in nonhuman primates. J Nucl Med. 2017; 58:982-988
Baum E, Cai Z, Bois F, Holden D, Lin SF, Lara-Jaime T, Kapinos M, Chen Y, Deuther-Conrad W, Fischer S, Dukic-Stefanovic S, Bunse P, Wünsch B, Brust P, Jia H, Huang Y
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Bridging from Brain to Tumor imaging: (S)- and (R)-[18F]Fluspidine for investigation of sigma-1 receptors in tumor-bearing mice. Molecules. 2018, 23:pii: E70
Kranz M, Bergmann R, Kniess T, Belter B, Neuber C, Cai Z, Deng G, Fischer S, Steinbach J, Zhou J, Huang H, Brust P, Deuther-Conrad W, Pietzsch J
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Increased sigma-1 receptor (Sig-1R) binding in the brain of unmedicated patients with acute major depressive disorder (MDD) using the novel Sig-1R-specific radioligand (–)-[18F]Fluspidine and PET. J. Nucl. Med. 2018; 59:551
Meyer PM, Strauß M, Becker G, Hesse S, Bednasch K, Ettrich B, Zientek F, Rullmann M, Wilke S, Luthardt J, Patt M, Wünsch B, Brust P, Sabri O
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Kinetic modeling of the new σ1 receptor ligand (-)[18F]Fluspidine in the human brain. Nuklearmedizin 2018; 57:V9
Becker GA, Meyer PM, Patt M, Hesse S, Luthardt J, Patt J, Rullmann M, Fischer S, Kluge A, Steinbach J, Wünsch B, Brust P, Sabri O
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Synthesis of substituted 1-alkylidenephthalanes via lithium-promoted 5-exodig cyclization. Eur. J. Org. Chem. 2018, 1806-1812
Bunse P, Würthwein EU, Wünsch B
