PMID- 29225193 OWN - NLM STAT- MEDLINE DCOM- 20180806 LR - 20190205 IS - 1879-0712 (Electronic) IS - 0014-2999 (Print) IS - 0014-2999 (Linking) VI - 820 DP - 2018 Feb 5 TI - Synthesis and in vitro characterization of a P2X7 radioligand [(123)I]TZ6019 and its response to neuroinflammation in a mouse model of Alzheimer disease. PG - 8-17 LID - S0014-2999(17)30792-6 [pii] LID - 10.1016/j.ejphar.2017.12.006 [doi] AB - The purinergic receptor P2X ligand-gated ion channel 7 (P2X7 receptor) is a promising imaging target to detect neuroinflammation. Herein, we report development of a potent iodinated radiotracer for P2X7 receptor, [(123)I]TZ6019. The radiosynthesis of [(123)I]TZ6019 was accomplished by allylic-tin precursor iodination using [(123)I]NaI with good radiochemical yield of 85% and high radiochemical purity of > 99%. Human embryonic kidney 293 (HEK-293) cell line stably transfected with the human P2X7 receptor was used to characterize the binding affinity of TZ6019 by fluorescence, radioactive competitive, and saturation binding assays. A radioligand competitive binding assay with [(123)I]TZ6019 demonstrated that the nonradioactive compound TZ6019 has an IC(50) value of 9.49 +/- 1.4nM, and the known P2X7 receptor compound GSK1482160 has an IC(50) value of 4.30 +/- 0.86nM, consistent with previous reports. The radioligand saturation binding assay and competitive assay revealed that [(123)I]TZ6019 specifically bound to the human P2X7 receptor with high affinity (K(i) = 6.3 +/- 0.9nM). In vitro autoradiography quantification with brain slices collected from 9-month old P301S tau transgenic mice along with wild type controls, revealed higher binding of [(123)I]TZ6019 (35% increase) in the brain of P301S transgenic mice (n = 3, p = 0.04) compared to wild type controls. The immunofluorescence microscopy confirmed that expression of P2X7 receptor was colocalized with astrocytes in the tauopathy P301S transgenic mice. [(123)I]TZ6019 has specific binding for P2X7 receptor and has great potential to be a radiotracer for screening new compounds and quantifying expression of P2X7 receptor in neuroinflammation related diseases. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Jin, Hongjun AU - Jin H AD - Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Han, Junbin AU - Han J AD - Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Resing, Derek AU - Resing D AD - Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Liu, Hui AU - Liu H AD - Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Yue, Xuyi AU - Yue X AD - Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Miller, Rebecca L AU - Miller RL AD - Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Schoch, Kathleen M AU - Schoch KM AD - Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Miller, Timothy M AU - Miller TM AD - Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Perlmutter, Joel S AU - Perlmutter JS AD - Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63110, USA. FAU - Egan, Terrance M AU - Egan TM AD - Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104, USA. FAU - Tu, Zhude AU - Tu Z AD - Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: tuz@mir.wustl.edu. LA - eng GR - R01 NS103988/NS/NINDS NIH HHS/United States GR - R21 MH092797/MH/NIMH NIH HHS/United States GR - R01 NS075321/NS/NINDS NIH HHS/United States GR - R01 NS103957/NS/NINDS NIH HHS/United States GR - R01 NS075527/NS/NINDS NIH HHS/United States GR - R01 GM112188/GM/NIGMS NIH HHS/United States GR - R33 MH092797/MH/NIMH NIH HHS/United States GR - R01 NS058714/NS/NINDS NIH HHS/United States PT - Journal Article DEP - 20171207 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Benzyl Compounds) RN - 0 (Ligands) RN - 0 (Pyrrolidines) RN - 0 (Receptors, Purinergic P2X7) RN - 0 (TZ6019) SB - IM MH - Alzheimer Disease/*metabolism MH - Animals MH - Astrocytes/metabolism MH - Benzyl Compounds/chemical synthesis/chemistry/*metabolism MH - Binding, Competitive MH - Brain/metabolism MH - Chemistry Techniques, Synthetic MH - Disease Models, Animal MH - Gene Expression Regulation MH - HEK293 Cells MH - Humans MH - Ligands MH - Mice MH - Pyrrolidines/chemical synthesis/chemistry/*metabolism MH - Radiochemistry MH - Receptors, Purinergic P2X7/*metabolism PMC - PMC5767129 MID - NIHMS928501 OTO - NOTNLM OT - I-123 OT - Neuroinflammation OT - P2X7 receptor OT - P301S COIS- Disclosure The authors do not have any conflict of interest. EDAT- 2017/12/12 06:00 MHDA- 2018/08/07 06:00 PMCR- 2019/02/05 CRDT- 2017/12/12 06:00 PHST- 2017/07/28 00:00 [received] PHST- 2017/11/21 00:00 [revised] PHST- 2017/12/04 00:00 [accepted] PHST- 2017/12/12 06:00 [pubmed] PHST- 2018/08/07 06:00 [medline] PHST- 2017/12/12 06:00 [entrez] PHST- 2019/02/05 00:00 [pmc-release] AID - S0014-2999(17)30792-6 [pii] AID - 10.1016/j.ejphar.2017.12.006 [doi] PST - ppublish SO - Eur J Pharmacol. 2018 Feb 5;820:8-17. doi: 10.1016/j.ejphar.2017.12.006. Epub 2017 Dec 7.