Original articles
Ying Zhang, Tao Wang, Xiaojun Zhang, Winnie Deuther-Conrad, Hualong Fu, Mengchao Cui, Jinming Zhang, Peter Brust, Yiyun Huang, Hongmei Jia. Discovery and development of brain-penetrant 18F-labeled radioligands for neuroimaging of the sigma-2 receptors[J]. Acta Pharmaceutica Sinica B, 2022, 12(3): 1406-1415

Discovery and development of brain-penetrant 18F-labeled radioligands for neuroimaging of the sigma-2 receptors
Ying Zhanga, Tao Wanga, Xiaojun Zhangb, Winnie Deuther-Conradc, Hualong Fua, Mengchao Cuia, Jinming Zhangb, Peter Brustc,e, Yiyun Huangd, Hongmei Jiaa
a. Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China;
b. Nuclear Medicine Department, Chinese PLA General Hospital, Beijing 100853, China;
c. Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Leipzig 04318, Germany;
d. PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520-8048, USA;
e. The L�beck Institute of Experimental Dermatology, University Medical Center Schleswig-Holstein, L�beck 23538, Germany
We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 (σ2) receptor ligands. Two ligands with high σ2 receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities, and evaluated in rodents. In biodistribution studies in male ICR mice, radioligand[18F]9, or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole, was found to display high brain uptake and high brain-to-blood ratio. Pretreatment of animals with the selective σ2 receptor ligand CM398 led to significant reductions in both brain uptake (29%-54%) and brain-to-blood ratio (60%-88%) of the radioligand in a dose-dependent manner, indicating high and saturable specific binding of[18F]9 to σ2 receptors in the brain. Further, ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of[18F]9 in the brain that is consistent with the distribution pattern of σ2 receptors. Dynamic positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for[18F]9 in the rat brain, along with appropriate tissue kinetics. Taken together, results from our current study indicated the novel radioligand[18F]9 as the first highly specific and promising imaging agent for σ2 receptors in the brain.
Key words:    Indole-based derivatives    σ2 receptor    Fluorine-18    Positron emission tomography    Neuroimaging   
Received: 2021-05-28     Revised: 2021-08-19
DOI: 10.1016/j.apsb.2021.08.029
Funds: This work was supported by the National Natural Science Foundation of China (No. 21876013) and Beijing Natural Science Foundation (7212203, China).
Corresponding author: Jinming Zhang,E-mai:zhangjm301@163.com;Yiyun Huang,E-mai:henry.huang@yale.edu;Hongmei Jia,E-mai:hmjia@bnu.edu.cn     Email:zhangjm301@163.com;henry.huang@yale.edu;hmjia@bnu.edu.cn
Author description:
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Ying Zhang
Tao Wang
Xiaojun Zhang
Winnie Deuther-Conrad
Hualong Fu
Mengchao Cui
Jinming Zhang
Peter Brust
Yiyun Huang
Hongmei Jia

[1] Gabitova L, Gorin A, Astsaturov I. Molecular pathways: sterols and receptor signaling in cancer. Clin Cancer Res 2014;20:28-34
[2] Yang K, Zeng C, Wang C, Sun M, Yin D, Sun T. Sigma-2 receptor-a potential target for cancer/Alzheimer's disease treatment via its regulation of cholesterol homeostasis. Molecules 2020;25:5439
[3] Chang TY, Yamauchi Y, Hasan MT, Chang C. Cellular cholesterol homeostasis and Alzheimer's disease. J Lipid Res 2017;58:2239-2254
[4] Matsushita Y, Nakagawa H, Koike K. Lipid metabolism in oncology: why it matters, how to research, and how to treat. Cancers 2021;13:474
[5] Mayengbam SS, Singh A, Pillai AD, Bhat MK. Influence of cholesterol on cancer progression and therapy. Transl Oncol 2021;14:101043
[6] Wellington CL. Cholesterol at the crossroads: Alzheimer's disease and lipid metabolism. Clin Genet 2004;66:1-16
[7] Lukiw WJ, Pappolla M, Pelaez RP, Bazan NG. Alzheimer's disease-a dysfunction in cholesterol and lipid metabolism. Cell Mol Neurobiol 2005;25:475-483
[8] Alon A, Schmidt HR, Wood MD, Sahn JJ, Martin SF, Kruse AC. Identification of the gene that codes for the σ2 receptor. Proc Natl Acad Sci Unit States Am 2017;114:7160-7165
[9] Bartz F, Kern L, Erz D, Zhu M, Gilbert D, Meinhof T, et al. Identification of cholesterol-regulating genes by targeted RNAi screening. Cell Metabol 2009;10:63-75
[10] Shen H, Li J, Xie X, Yang H, Zhang M, Wang B, et al. BRD2 regulation of sigma-2 receptor upon cholesterol deprivation. Life Sci Alliance 2020;4:e201900540
[11] Zeng C, Riad A, Mach RH. The biological function of sigma-2 receptor/TMEM97 and its utility in PET imaging studies in cancer. Cancers 2020;12:1877
[12] Mach RH, Smith CR, Al-Nabulsi I, Whirrett BR, Childers SR, Wheeler KT. σ2 receptors as potential biomarkers of proliferation in breast cancer. Cancer Res 1997;57:156-161
[13] Al-Nabulsi I, Mach RH, Wang LM, Wallen CA, Keng PC, Sten K, et al. Effect of ploidy, recruitment, environmental factors, and tamoxifen treatment on the expression of sigma-2 receptors in proliferating and quiescent tumour cells. Br J Cancer 1999;81:925-933
[14] Wheeler KT, Wang LM, Wallen CA, Childers SR, Cline JM, Keng PC, et al. Sigma-2 receptors as a biomaker of proliferaion in solid tumours. Br J Cancer 2000;82:1223-1232
[15] Riad A, Zeng C, Weng CC, Winters H, Xu K, Makvandi M, et al. Sigma-2 receptor/TMEM97 and PGRMC-1 increase the rate of internalization of LDL by LDL receptor through the formation of a ternary complex. Sci Rep 2018;8:16845
[16] Riad A, Lengyel-Zhand Z, Zeng C, Weng CC, Lee VM, Trojanowski JQ, et al. The sigma-2 receptor/TMEM97, PGRMC1, and LDL receptor complex are responsible for the cellular uptake of Abeta42 and its protein aggregates. Mol Neurobiol 2020;57:3803-3813
[17] Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, et al. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers II: sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One 2014;9:e111899
[18] Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, et al. Alzheimer's therapeutics targeting amyloid beta 1-42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One 2014;9:e111898
[19] Grundman M, Morgan R, Lickliter JD, Schneider LS, DeKosky S, Izzo NJ, et al. A phase 1 clinical trial of the sigma-2 receptor complex allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer's disease. Alzheimers Dement 2019;5:20-26
[20] Izzo NJ, Yuede CM, LaBarbera KM, Limegrover CS, Rehak C, Yurko R, et al. Preclinical and clinical biomarker studies of CT1812: a novel approach to Alzheimer's disease modification. Alzheimers Dement 2021;17:1365-1382
[21] Huang YS, Lu HL, Zhang LJ, Wu Z. Sigma-2 receptor ligands and their perspectives in cancer diagnosis and therapy. Med Res Rev 2014;34:532-566
[22] Mach RH, Zeng C, Hawkins WG. The σ2 receptor: a novel protein for the imaging and treatment of cancer. J Med Chem 2013;56:7137-7160
[23] Zeng C, McDonald ES, Mach RH. Molecular probes for imaging the sigma-2 receptor: in vitro and in vivo imaging studies. Handb Exp Pharmacol 2017;244:309-330
[24] Dehdashti F, Laforest R, Gao F, Shoghi KI, Aft RL, Nussenbaum B, et al. Assessment of cellular proliferation in tumors by PET using 18F-ISO-1. J Nucl Med 2013;54:350-357
[25] McDonald ES, Doot RK, Young AJ, Schubert EK, Tchou J, Pryma DA, et al. Breast cancer 18F-ISO-1 uptake as a marker of proliferation status. J Nucl Med 2020;61:665-670
[26] Abramson Cancer Center of the University of Pennsylvania. Imaging of in vivo sigma-2 receptor expression with 18F-ISO-1 positron emission tomography in metastatic breast cancer. ClinicalTrials.gov Identifier: NCT03057743, 2017
[27] Tu Z, Xu J, Jones LA, Li S, Dumstorff C, Vangveravong S, et al. Fluorine-18-labeled benzamide analogues for imaging the σ2 receptor status of solid tumors with positron emission tomography. J Med Chem 2007;50:3194-3204
[28] Mesangeau C, Amata E, Alsharif W, Seminerio MJ, Robson MJ, Matsumoto RR, et al. Synthesis and pharmacological evaluation of indole-based sigma receptor ligands. Eur J Med Chem 2011;46:5154v61
[29] Wang L, Ye J, He Y, Deuther-Conrad W, Zhang J, Zhang X, et al. 18F-Labeled indole-based analogs as highly selective radioligands for imaging sigma-2 receptors in the brain. Bioorg Med Chem 2017;25:3792-3802
[30] Fan C, Jia H, Deuther-Conrad W, Brust P, Steinbach J, Liu B. Novel 99mTc labeled σ receptor ligand as a potential tumor imaging agent. Sci China Ser B Chem 2006;49:169-176
[31] Bautista-Aguilera OM, Budni J, Mina F, Medeiros EB, Deuther-Conrad W, Entrena JM, et al. Contilisant, a tetratarget small molecule for Alzheimer's disease therapy combining cholinesterase, monoamine oxidase inhibition, and H3R antagonism with S1R agonism profile. J Med Chem 2018;61:6937-6943
[32] Li Y, Wang X, Zhang J, Deuther-Conrad W, Xie F, Zhang X, et al. Synthesis and evaluation of novel 18F-labeled spirocyclic piperidine derivatives as σ1 receptor ligands for positron emission tomography imaging. J Med Chem 2013;56:3478-3491
[33] Patel S, Gibson R. In vivo site-directed radiotracers: a mini-review. Nucl Med Biol 2008;35:805-815
[34] Intagliata S, Sharma A, King TI, Mesangeau C, Seminerio M, Chin FT, et al. Discovery of a highly selective sigma-2 receptor ligand, 1-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-3-methyl-1H-benzo[d]imidazole-2(3H)-one (CM398), with drug-like properties and antinociceptive effects in vivo. AAPS J 2020;22:94
[35] Kreisl WC, Liow JS, Kimura N, Seneca N, Zoghbi SS, Morse CL, et al. P-glycoprotein function at the blood-brain barrier in humans can be quantified with the substrate radiotracer 11C-N-desmethyl-loperamide. J Nucl Med 2010;51:559-566
[36] Abate C, Selivanova SV, Muller A, Kramer SD, Schibli R, Marottoli R, et al. Development of 3,4-dihydroisoquinolin-1(2H)-one derivatives for the Positron Emission Tomography (PET) imaging of σ2 receptors. Eur J Med Chem 2013;69:920-930
[37] Tian J, He Y, Deuther-Conrad W, Fu H, Xie F, Zhang Y, et al. Synthesis and evaluation of new 1-oxa-8-azaspiro[4.5]decane derivatives as candidate radioligands for sigma-1 receptors. Bioorg Med Chem 2020;28:115560
[38] Sahn JJ, Mejia GL, Ray PR, Martin SF, Price TJ. Sigma 2 receptor/Tmem97 agonists produce long lasting antineuropathic pain effects in mice. ACS Chem Neurosci 2017;8:1801-1811
[39] Lever JR, Miller DK, Green CL, Fergason-Cantrell EA, Watkinson LD, Carmack TL, et al. A selective sigma-2 receptor ligand antagonizes cocaine-induced hyperlocomotion in mice. Synapse 2014;68:73-84
[40] Soeby KK, Mikkelsen JD, Meier E, Thomsen C. Lu 28-179 labels a σ2-site in rat and human brain. Neuropharmacology 2002;43:95-100
[41] He Y, Xie F, Ye J, Deuther-Conrad W, Cui B, Wang L, et al. 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;60:4161-4172
[42] Chen YY, Wang X, Zhang JM, Deuther-Conrad W, Zhang XJ, Huang Y, et al. Synthesis and evaluation of a 18F-labeled spirocyclic piperidine derivative as promising σ1 receptor imaging agent. Bioorg Med Chem 2014;22:5270-5278
[43] Leitner ML, Hohmann AG, Patrick SL, Walker JM. Regional variation in the ratio of σ1 to σ2 binding in rat brain. Eur J Pharmacol 1994;259:65-69
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