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JP-7856960-B2 - TSPO binder

JP7856960B2JP 7856960 B2JP7856960 B2JP 7856960B2JP-7856960-B2

Inventors

  • サザーランド アンドリュー
  • ピムロット サリー
  • タヴァレス アドリアナ
  • ルカテリ クリストフ

Assignees

  • ザ ユニヴァーシティー コート オブ ザ ユニヴァーシティー オブ グラスゴー
  • ザ ユニヴァーシティ コート オブ ザ ユニヴァーシティ オブ エディンバラ

Dates

Publication Date
20260512
Application Date
20240401
Priority Date
20180622

Claims (13)

  1. Formula (IV): Formula (IV) Compounds thereof, as well as their salts, solvates, and radiolabeled forms.
  2. The compound according to claim 1, wherein the compound is a compound of formula (R-IV). Formula (R-IV)
  3. For use in the preparation of the compound of formula (I), Equation (I) Use of a compound of formula (III) or (IV). Formula (III) Formula (IV)
  4. The use according to claim 3, wherein the compound of formula (III) or (IV) is for use in the preparation of the compound of formula (II). Formula (II)
  5. The use according to claim 3 or 4, wherein the compound of formula (III) is the compound of formula (R-III), or the compound of formula (IV) is the compound of formula (R-IV). Formula (R-III) Formula (R-IV)
  6. A method for preparing a compound of formula (I), comprising the step of substituting bromine in a compound of formula (III) with fluorine, or substituting chlorine in a compound of formula (IV) with fluorine. Equation (I) Formula (III) Formula (IV)
  7. A method for preparing the compound of formula (II), wherein the method involves the bromine of the compound of formula (III) The method according to claim 6, comprising the step of substituting with 18-fluorine, or substituting the chlorine of a compound of formula (IV) with 18-fluorine. Formula (II)
  8. The method according to claim 6 or 7, wherein the compound of formula (IV) is prepared from the compound of formula (III) by substituting bromine with chlorine in the compound of formula (III).
  9. The method according to any one of claims 6 to 8, wherein the compound of formula (III) is the compound of formula (R-III), or the compound of formula (IV) is the compound of formula (R-IV). Formula (R-III) Formula (R-IV)
  10. A kit comprising a compound of formula (III) or formula (IV) and a fluorine anion. Formula (III) Formula (IV)
  11. The kit according to claim 10, wherein the fluorine anion is supplied as a fluorine salt.
  12. The use of a fluorine anion in the preparation of a compound of formula (I) by substituting bromine in a compound of formula (III) with fluorine, or by substituting chlorine in a compound of formula (IV) with fluorine. Equation (I) Formula (III) Formula (IV)
  13. The use according to claim 12, wherein the fluorine anion is supplied as a fluorine salt.

Description

Related Application This application claims the interests and priority of British Patent No. 1810312.7, filed on 22 June 2018 (22.06.2018), the contents of which are incorporated herein by reference in their entirety. Field of Invention The present invention provides compounds for use in binding with TSPO, methods for preparing such compounds, methods for binding the compounds with TSPO, and methods for detecting compounds bound to TSPO. The 18 kDa transporter protein (TSPO, translocator protein), officially known as the peripheral diazepine receptor (Papadopoulos et al. Trends Pharmacol. Sci. 27, 402-409 (2006)), is expressed within the outer mitochondrial membrane and is involved in cholesterol transport and steroid synthesis (Lacapere Steroids 68, 569-585 (2003)). TSPO is also found in microglia in the brain (Wilms et al. Neurobiol. Dis. 14, 417-424 (2003) and Cosenza-Nashat et al. It has been found to be highly expressed in inflammatory cells such as macrophages (Fujimura et al. Atherosclerosis 201, 108-111 (2008) and Bird et al. Atherosclerosis 210, 388-391 (2010)) and peripheral macrophages, and therefore has been considered useful as a marker of inflammation in pathology throughout the body. Increased TSPO expression has been demonstrated in neurodegenerative diseases such as dementia and Parkinson's disease (Dupont et al. Int. J. Mol. Sci. 18, 785 (2017)), and in cardiovascular diseases, specifically in atherosclerotic plaques (Bird et al. Atherosclerosis 210, 388-391 (2010)) and in the heart after myocardial infarction (Thackeray et al. J. Am. Coll. Cardiol. 71, 263-275 (2018)). Therefore, a successful imaging approach targeting TSPO with PET has significant clinical value in a wide range of pathologies. In addition to its usefulness as a marker of inflammation, TSPO has recently been demonstrated to play a role in neuroprotection (Thackeray et al. J. Am. Coll. Cardiol. 71, 263-275 (2018)) and cardioprotection (Schalle et al. J. Pharmacol. Exp. Ther. 333, 696-706 (2010) and Paradis et al. Cardiovasc. Res. 98, 420-427 (2013)). Therefore, it further expands the scope of application of non-invasive TSPO imaging in the context of disease onset and progression, as well as for targeting disease-modifying therapies. In the field of positron emission tomography (PET) imaging of inflammation, TSPO is one of the most widely explored targets. The prototype TSPO PET radiotracer developed decades ago is 11C -PK11195 (Charbonneau et al. Circulation 73, 476-483 (1986)). This radiotracer has limited the widespread adoption of clinical routines due to the short half-life (20 minutes) of the radioisotope, which requires hospitals to have on-site cyclotron facilities. In addition, 11C -PK11195 exhibits relatively high nonspecific binding (Chauveau et al. Eur. J. Nucl. Med. Mol. Imaging 35, 2304-2319 (2008)). Therefore, as summarized in a recently published review (Alam et al. Med. Mol. Imaging (2010). 51, 283-296 (2017)), considerable effort has been made to create a novel family of TSPO radioactive tracers with improved characteristics. Despite these developments, 11C -PK11195 is still regularly used as a clinical research tool. This is a result of the high inter-individual binding of all TSPO radiotracers synthesized and investigated after the development of 11C -PK11195, and is now publicly known to be caused by the genetic polymorphism rs6971, as identified in the original study by Owen et al. (Owen et al. J. Cereb. Blood Flow Metab. 32, 1-5 (2012)). This common genetic polymorphism means that approximately 10% of the human population classified as low-affinity binders (LABs) are unimagingable with second-generation radiotracers, and the remainder of the human population division between mixed-affinity binders and high-affinity binders (MABs and HABs) requires genetic screening and complex post-imaging correction. There is a wide range of variability in the sensitivity of second-generation ligands to the rs6971 genetic polymorphism. For example, 11C -PBR28 has a LAB:HAB ratio of 55 in vitro (Owen et al. J. Nucl. Med. 52, 24-32 (2011)), while more recently designed radiotracers 11C -ER176 and PK11195 analogs have a ratio of 1.3 in vitro (Zanotti-Fregonara et al. ACS Chem. Neurosci. (2014), doi:10.1021/cn500138n). Therefore, to date, PK11195 remains the only TSPO radiotrace whose insensitivity to the rs6971 polymorphism in the human brain has been reliably demonstrated (Owen et al. J. Nucl. Med. 52, 24-32 (2011) and Owen et al. J. Cereb. Blood Flow Metab. 30, 1608-18 (2010)). Further binders for TSPO that also demonstrate insensitivity to the rs6971 polymorphism are needed. Papadopoulos et al. Trends Pharmacol. Sci. 27, 402-409 (2006)Lacapere Steroids 68, 569-585 (2003)Wilms et al. Neurobiol. Dis. 14, 417-424 (2003)Cosenza-Nashat et al. Neuropathol. Appl. Neurobiol. 35, 306-328 (2009)Fujimura et al. Atherosclerosis 201, 108-111 (2008)Bird et al. Atherosclerosis 210, 388-391 (2010)Dupont et al. Int. J. Mol. Sci. 18,