Development of ¹⁸F-labelled PET radiotracers for the imaging of σ receptors in cancer and brain diseases

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• σ1 receptor

Unlike classical plasma-membrane bound neurotransmitter receptors the σ₁ receptor resides mainly at the mitochondria-associated membranes of the endoplasmatic reticulum and interacts specifically with proteins involved in the homeostasis of the intracellular Ca²⁺-concentration. Currently σ₁ receptor is considered as novel biological target for the pharmacological treatment of cancer and several brain diseases, e.g. depression, anxiety and neurodegeneration. This project is focused on the development of σ₁ receptor imaging by PET which is useful to examine the biological function and therapeutic potential of σ₁ receptor for oncology application and treatment of neurological and psychiatric disorders.

 

	Radiosynthesis and ex vivo autoradiographic images of the distribution of a series of 18F-labelled fluoroalkyl-substituted spirocyclic piperidines in the brain of CD1 mice at 45 min post injection of the respective radiotracer. The localization of the radiotracers correlates with σ1 receptor-rich regions such as the area of the facial nucleus, the dorsolateral and lateral periaqueductal gray, the dorsomedial hypothalamic area, and the cerebellum. In comparison to [18F]WMS1813 and [18F]WMS1847 the fluoroethyl-substituted radiotracer [18F]Fluspidine provided superior target-to-nontarget tissue ratios and is therefore chosen for further preclinical development.

Preclinical dosimetry and translation into human applications

	Molecules 2016, 21(9), 1164
	Left: PET image of a female CD-1 mouse after injection of (R)-(+)- or (S)-(−)-[18F]fluspidine, respectively. The human radiation dose of both enantiomers of [18F]fluspidine was assessed from ex vivo biodistribution and PET/MRI data in mice after extrapolation to the human scale. Right: PET of a male volunteer after application of (S)-(−)-[18F]fluspidine. The first-in-human study confirmed that the radiation risk of (S)-(−)-[18F]fluspidine imaging is within acceptable limits.

• σ2 receptor

The sigma-2 (σ2) receptor (molecular weight ∼ 21.5 kDa) is believed to play important roles in the regulation of cellular differentiation. σ2 receptors are expressed at rather high densities in many tumors. Their overexpression and higher abundance than σ1 receptors has been shown in renal and colon carcinomas suggesting that sigma receptor expression could be a biomarker of cellular proliferation and that tumors might be visualized using radiolabeled sigma receptor ligands and medical imaging techniques. Moreover, the σ2 receptor interacts with Ca2+ channels and participates in various central nervous system (CNS) processes, with potential impact on learning and memory.Hence it is also considered a therapeutic target for the treatment of brain disorders.

The σ2 selective ligands, which have been developed into PET tracers belong to three classes of compounds: (1) flexible benzamides with a tetramethylene or an ethylene spacer between the N-atoms, (2) 1,4-disubstituted piperazines derived from PB 28, and (3) spirocyclic compounds derived from siramesin. The objective of an ongoing project is the development of ¹⁸F-labeled PET tracers suitable for imaging of σ2 receptors in the human brain. At present, a suitable radiotracer for clinical σ2 eceptor imaging with PET is not available. The development of a PET tracer is an iterative process, which requires a multidimensional optimization taking affinity, selectivity, lipophilicity, stability, radiochemical availability and pharmacokinetic properties including blood-brain barrier penetration and biotransformation of the potential radiotracer into account.

Partners

• Department of Pharmaceutical and Medicinal Chemistry (Head: Prof. Bernhard Wünsch), Westfälische Wilhelms-Universität Münster, Germany

• Department of Nuclear Medicine (Head: Prof. Osama Sabri), Universität Leipzig, Germany

• Key Laboratory of Radiopharmaceuticals (Head: Prof. Hong-Mei Jia), Bejing Normal University, China

• PET Center (Head: Prof. Yiyun Huang), Department of Radiology and Biomedical Imaging, Yale University, New Haven, USA

Financial support by

• Deutsche Forschungsgemeinschaft - DFG
  

Publications

• Kranz M, Bergmann R, Kniess T, Belter B, Neuber C, Cai Z, Deng G, Fischer S , Steinbach J, Zhou J, Huang Y, Brust P, Deuther-Conrad W, Pietzsch J. Bridging from brain to tumor imaging: (S)- and (R)-[¹⁸F]fluspidine for investigation of sigma-1 receptors in tumor-bearing mice. Molecules 2018; 23(3), pii: E702.

• Weber F, Brust P, Laurini E, Pricl S, Wünsch B. Fluorinated PET Tracers for Molecular Imaging of σ1 Receptors in the Central Nervous System. Adv Exp Med Biol. 2017;964:31-48.

• Wang L, Ye J, He Y, Deuther-Conrad W, Zhang J, Zhang X, Cui M, Steinbach J, Huang Y, Brust P, Jia H. 18F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain. Bioorg Med Chem. 2017, 25(14):3792-3802.

• He Y, Xie F, Ye J, Deuther-Conrad W, Cui B, Wang L, Lu J, Steinbach J, Brust P, Huang Y, Lu J, Jia H. 1-(4-[18F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine: A Novel Suitable Radioligand with Low Lipophilicity for Imaging σ1 Receptors in the Brain. J Med Chem. 2017, 60(10):4161-4172.

• 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. PET Imaging Evaluation of Four σ1 Radiotracers in Nonhuman Primates. J Nucl Med. 2017, 58(6):982-988.

• 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. Evaluation of the Enantiomer Specific Biokinetics and Radiation Doses of [(18)F]Fluspidine-A New Tracer in Clinical Translation for Imaging of σ₁ Receptors. Molecules. 2016, 21(9). pii: E1164.

• Li D, Chen Y, Wang X, Deuther-Conrad W, Chen X, Jia B, Dong C, Steinbach J, Brust P, Liu B, Jia H. (99m)Tc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma-2 Receptor Ligands for Tumor Imaging. J Med Chem. 2016, 59(3):934-46.

• Chen YY, Wang X, Zhang JM, Deuther-Conrad W, Zhang XJ, Huang Y, Li Y, Ye JJ, Cui MC, Steinbach J, Brust P, Liu BL, Jia HM. Synthesis and evaluation of a 18F-labeled spirocyclic piperidine derivative as promising σ1 receptor imaging agent. Bioorg Med Chem. 2014, 22(19):5270-8.

• Wang X, Li D, Deuther-Conrad W, Lu J, Xie Y, Jia B, Cui M, Steinbach J, Brust P, Liu B, Jia H. Novel cyclopentadienyl tricarbonyl (99m)tc complexes containing 1-piperonylpiperazine moiety: potential imaging probes for sigma-1 receptors. J Med Chem. 2014, 57(16):7113-25.

• Brust P, Deuther-Conrad W, Becker G, Patt M, Donat CK, Stittsworth S, Fischer S, Hiller A, Wenzel B, Dukic-Stefanovic S, Hesse S, Steinbach J, Wünsch B, Lever SZ, Sabri O. Distinctive in vivo kinetics of the new σ1 receptor ligands (R)-(+)- and (S)-(-)-18F-fluspidine in porcine brain. J Nucl Med. 55(2014) 1730-6.

• Maisonial-Besset A, Funke U, Wenzel B, Fischer S, Holl K, Wünsch B, Steinbach J, Brust P. 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. 84 (2014) 1-7.

• Holl K, Falck E, Köhler J, Schepmann D, Humpf HU, Brust P, Wünsch B. Synthesis, characterization, and metabolism studies of fluspidine enantiomers. ChemMedChem. 8(2013) 2047-56.

• Brust P, Deuther-Conrad W, Lehmkuhl K, Jia H, Wünsch B. Molecular imaging of σ1 receptors in vivo: current status and perspectives. Curr Med Chem. 21(2014) 35-69.

• Li Y, Wang X, Zhang J, Deuther-Conrad W, Xie F, Zhang X, Liu J, Qiao J, Cui M, Steinbach J, Brust P, Liu B, Jia H. Synthesis and evaluation of novel (18)F-labeled spirocyclic piperidine derivatives as σ1 receptor ligands for positron emission tomography imaging. J Med Chem. 56 (2013) 3478-91.

• Wang X, Li Y, Deuther-Conrad W, Xie F, Chen X, Cui M-C,  Zhang,X-J,  Zhang J-M, Steinbach J, Brust P, Liu B-L,  Jia H-M. Synthesis and biological evaluation of ¹⁸F-labeled fluoro-oligo-ethoxylated 4-benzylpiperazine derivatives for sigma-1 receptor imaging. Bioorg. Med. Chem. 21 (2013) 215-222.

• Chen X, Cui MC, Deuther-Conrad W, Tu YF, Ma T, Xie Y, Jia B, Li Y, Xie F, Wang X, Steinbach J, Brust P, Liu BL, Jia HM.Synthesis and biological evaluation of a novel 99mTc cyclopentadienyl tricarbonyl complex ([(Cp-R)99mTc(CO)3]) for sigma-2 receptor tumor imaging. Bioorg Med Chem Lett. 22 (2012) 6352-7.

• Maisonial A, Grosse Maestrup E, Wiese C, Hiller A, Schepmann D, Deuther-Conrad W, Fischer S, Brust P, Wünsch B. Synthesis, radiofluorination and pharmacological evaluation of fluoromethyl substituted spirocyclic PET tracers for labeling of σ1 receptors in the central nervous system and comparison with longer homologues. Bioorg. Med. Chem. 20 (2012) 257-269.

• Maisonial A, Grosse Maestrup E, Fischer S, Hiller A, Scheunemann M, Wiese C, Schepmann D, Steinbach J, Deuther-Conrad W, Wünsch B, Brust P. A 18F-labeled fluorobutyl-substituted spirocyclic piperidine derivative as a selective radioligand for PET Imaging of sigma1 receptors. ChemMedChem. 2011,6(8):1401-10.

• Fischer S, Wiese C, Grosse Maestrup E, Hiller A, Deuther-Conrad W, Scheunemann M, Schepmann D, Steinbach J, Wünsch B, Brust P.Molecular imaging of σ receptors: synthesis and evaluation of the potent σ1 selective radioligand [18F]fluspidine.Eur J Nucl Med Mol Imaging. 2011,38(3):540-51.

• Grosse Maestrup E, Fischer S, Wiese C, Schepmann D, Hiller A, Deuther-Conrad W, Steinbach J, Wünsch B, Brust P. Evaluation of spirocyclic 3-(3-fluoropropyl)-2-benzofurans as sigma1 receptor ligands for neuroimaging with positron emission tomography. J Med Chem. 2009,52(19):6062-72.

• Grosse Maestrup E, Wiese C, Schepmann D, Hiller A, Fischer S, Scheunemann M, Brust P, Wünsch B. Synthesis of spirocyclic sigma1 receptor ligands as potential PET radiotracers, structure-affinity relationships and in vitro metabolic stability. Bioorg Med Chem. 2009,17(10):3630-41.