WO2015103946A1 - Dérivé d'acide gras supérieur marqué avec du technétium-99m - Google Patents

Dérivé d'acide gras supérieur marqué avec du technétium-99m Download PDF

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Publication number
WO2015103946A1
WO2015103946A1 PCT/CN2015/000087 CN2015000087W WO2015103946A1 WO 2015103946 A1 WO2015103946 A1 WO 2015103946A1 CN 2015000087 W CN2015000087 W CN 2015000087W WO 2015103946 A1 WO2015103946 A1 WO 2015103946A1
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compound
fatty acid
higher fatty
acid derivative
labeled
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PCT/CN2015/000087
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English (en)
Chinese (zh)
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张华北
薛甜
李香
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北京师范大学
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Publication of WO2015103946A1 publication Critical patent/WO2015103946A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids

Definitions

  • the invention relates to a fatty acid compound in the field of organic chemistry and medicinal chemistry, in particular to a yttrium-99m labeled higher fatty acid derivative.
  • Cardiovascular and cerebrovascular diseases are a common disease that seriously threatens human health. At present, there are more than 270 million people with cardiovascular and cerebrovascular diseases in China. China is dying of nearly 3 million cardiovascular and cerebrovascular diseases every year, accounting for 51% of the total cause of death in China every year. %. However, it takes only a few minutes from asymptomatic arteriosclerosis to symptomatic arteriosclerosis. If the early diagnosis of the disease can be achieved, the mortality rate of the disease can be greatly reduced, and it will have a positive impact on the overall situation of building a well-off society in China. Currently, PET/SPECT-based radiopharmaceuticals are considered to be the best way to achieve early diagnosis, focusing on the use of the most medically advanced and sensitive radiological diagnostic methods available today.
  • Myocardial metabolic activity is the most reliable marker of myocardial cell survival, so the most sensitive method for diagnosing myocardial survival is myocardial metabolic imaging.
  • the fatty acid myocardial metabolism reflects the function of mitochondria and fatty acid oxidases in cardiomyocytes, while glucose metabolism reflects the function of Na+/K+ pump in myocardial cell membrane. Therefore, fatty acid myocardial metabolic imaging can more accurately reflect myocardium than FDG myocardial metabolic imaging. Cell viability.
  • Fatty acid metabolism imaging can reflect the shape and metabolism of the heart, and can locate the location, extent and extent of myocardial ischemia and its necrosis.
  • Long-chain fatty acids are the main energizing substances in the myocardium. In the fasted state, the metabolism of long-chain fatty acids is accelerated, and in the non-fasted state, the oxidative metabolism slows down. When the heart muscle is weak or infarcted, the lesion has a significant metabolic difference from the normal myocardium. The metabolic rate of the myocardial lesion is slower than that of the normal site. This feature makes long-chain fatty acids a key factor in the early diagnosis of heart disease. Long-chain fatty acids are labeled with radionuclides, and PET/SPECT technology can be used to clearly determine whether myocardial lesions occur.
  • Fatty acid-based myocardial metabolic imaging agents labeled with radionuclide ⁇ -99m can be used to study the metabolism and function of myocardial tissue, and have important theoretical and practical significance in the study of nuclear cardiology.
  • a ⁇ -99m-labeled higher fatty acid derivative having the formula of the ⁇ -99m-labeled higher fatty acid derivative
  • n b + n c is not more than 20.
  • n b is 1 to 16 and n c is 1 to 16.
  • n 1 to n 12 are integers, n 1 is 1 to 16, n 2 is 1 to 18, n 3 is 1 to 16, n 4 is 0 to 16, n 5 is 0 to 16, and n 6 is 1. ⁇ 16, n 7 is 1 to 18, n 8 is 1 to 16, n 9 is 0 to 18, n 10 is 0 to 15, n 11 is 0 to 15, and n 12 is 0 to 16.
  • n 1 to n 12 are integers, n 1 is 2 to 13, n 2 is 10 to 16, n 3 is 1 to 6, n 4 is 8 to 11, n 5 is 1 to 5, and n 6 is 3. ⁇ 8, n 7 is 3 to 8, n 8 is 1 to 12, n 9 is 2 to 10, n 10 is 1 to 10, n 11 is 1 to 10, and n 12 is 1 to 6.
  • the present invention provides a quinone-99m-labeled higher fatty acid derivative, which has the main beneficial effect of increasing myocardial uptake and prolonging myocardial retention by introducing a sulfonyl group and a thiophene ring into a long-chain fatty acid, and at the same time greatly Reduced blood background.
  • Figure 3 is a radio-HPLC diagram of a rat metabolite extract in Example 8 of the present invention.
  • Figure 4 is an ESI-MS spectrum of rat metabolites.
  • a ⁇ -99m-labeled higher fatty acid derivative according to an embodiment of the present invention wherein the ⁇ -99m-labeled higher fatty acid derivative has the formula
  • X -, S;
  • R H;
  • n a ⁇ n c are integers, n a is 0-15, n b is 0 ⁇ 16, n c is 0 to 16, n d is 0 or 1; and when n d is 0, A is preferably SO 2 .
  • the structure of the ⁇ -99m-labeled higher fatty acid derivative is preferably:
  • n 1 to n 12 are integers, n 1 is 1 to 16, n 2 is 1 to 18, n 3 is 1 to 16, n 4 is 0 to 16, n 5 is 0 to 16, and n 6 is 1. ⁇ 16, n 7 is 1 to 18, n 8 is 1 to 16, n 9 is 0 to 18, n 10 is 0 to 15, n 11 is 0 to 15, and n 12 is 0 to 16; wherein n 1 ⁇ Preferred values of n 12 are: n 1 : 2 to 13, n 2 : 10 to 16, n 3 : 1 to 6, n 4 : 8 to 11, n 5 : 1 to 5, and n 6 : 3 to 8, n 7 : 3 to 8, n 8 : 1 to 12, n 9 : 2 to 10, n 10 : 1 to 10, n 11 : 1 to 10, and n 12 : 1 to 6.
  • the preferred preparation routes of the above five types of compounds are as follows.
  • the NMR data of the compound VI are: 1 H-NMR: 1.25 (m, 12H), 1.63 (m, 4H), 2.62 (m, 4H), 2.75 (t, 2H), 3.10 (t, 2H), 3.63 (s) , 3H), 4.13 (s, 5H), 4.43 (s, 2H), 4.73 (s, 2H), 4.73 (s, 2H), 6.79 (s, 1H), 7.45 (s, 1H).
  • the element ⁇ marked in the compound VII does not have a corresponding stable ruthenium compound as a correspondence to determine the structure and peak time of the radioactive cesium, in order to determine the peak time of VII, an element similar to the element ⁇ is selected (Re The compound VI is labeled to determine the structure of the compound VII, and the procedure is as follows.
  • the biodistribution of the compound VII is characterized by a higher initial myocardial uptake, reaching 20.70 ⁇ 0.30% ID/g after 1 min of injection, and rapid elution at 1-5 min, reaching at 5 min. 7.69% ID/g; after 5 min, the elution rate became slower, from 7.69% ID/g at 5 min to 6.47% ID/g at 30 min; at 30-60 min, the elution rate became faster again, and decreased to 3.06% at 60 min. /g.
  • the elution rate is slower than the current internationally good 99m Tc-CPTT-PA and 99m Tc-CPTT-16-oxo-HDA, indicating that the introduction of the thiophene ring into the ⁇ -99m labeled fatty acid chain has played a role in Prolonging the residence time and increasing the polarity of the compound, thereby increasing myocardial uptake and prolonging the retention time of the drug.
  • the compound showed a faster elution in the myocardium, from 30.71% ID/g at 1 min to 0.6% ID/g at 60 min, and the ratio of distribution in heart and blood reached a maximum of 9.24 at 30 min. It can be seen that this compound is an important potential drug for myocardial metabolism.
  • Example 7 Metabolic analysis of compound VII prepared in Example 4 in mice
  • Non-radioactive sputum-labeled precursors were generally used in place of radiopharmaceuticals for 30 minutes after injection into female SD rats (about 250 g) by tail vein for metabolic analysis.
  • the heart extract was filtered through a filter membrane to remove most of the tissue, then the solvent was removed and the macromolecules such as proteins were sedimented by ethanol and centrifuged.
  • the extract was spun dry and then rinsed on a Whatman solid phase extraction column (60 mg/3 mL). The extract was washed with methanol and washed under reduced pressure, and dissolved in methanol for mass spectrometry (ESI-MS) analysis. As shown in Fig.
  • ESI-MS mass spectrometry

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un dérivé d'acide gras supérieur marqué avec du technétium-99m qui est un médicament du métabolisme à base d'acide gras de chaîne longue. Le médicament du métabolisme à base d'acide gras de chaîne longue introduit un noyau sulfonyle et thiophène dans l'acide gras de chaîne longue pour réduire au final la liposolubilité des molécules, augmenter l'absorption du médicament dans le myocarde et prolonger le temps de rétention du médicament dans le myocarde.
PCT/CN2015/000087 2014-01-10 2015-02-09 Dérivé d'acide gras supérieur marqué avec du technétium-99m WO2015103946A1 (fr)

Applications Claiming Priority (2)

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CN201410010571.3 2014-01-10
CN201410010571.3A CN103772440B (zh) 2014-01-10 2014-01-10 一种锝‑99m标记的高级脂肪酸衍生物

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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107674098B (zh) * 2017-06-26 2021-12-07 中国医学科学院阜外医院 一类含芳基硼酸的99mTc配合物及其药盒配方和应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018908A1 (fr) * 1990-06-01 1991-12-12 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin COMPLEXES 99mTc DE CARBONYLE DE CYCLOPENTADIENYLE, PROCEDE POUR LEUR FABRICATION, AINSI QUE LEUR UTILISATION DANS LE DIAGNOSTIC MEDICAL
WO1997047328A1 (fr) * 1996-06-13 1997-12-18 Nycomed Amersham Plc Synthese d'analogues de ferrocenyl phenyltropane et leur radio-transformation en neuro-sondes au technetium pour la cartographie de sites de reabsorption des monoamines
CN102311459A (zh) * 2011-06-03 2012-01-11 北京师范大学 新型锝-99m标记的高级脂肪酸衍生物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991018908A1 (fr) * 1990-06-01 1991-12-12 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin COMPLEXES 99mTc DE CARBONYLE DE CYCLOPENTADIENYLE, PROCEDE POUR LEUR FABRICATION, AINSI QUE LEUR UTILISATION DANS LE DIAGNOSTIC MEDICAL
WO1997047328A1 (fr) * 1996-06-13 1997-12-18 Nycomed Amersham Plc Synthese d'analogues de ferrocenyl phenyltropane et leur radio-transformation en neuro-sondes au technetium pour la cartographie de sites de reabsorption des monoamines
CN102311459A (zh) * 2011-06-03 2012-01-11 北京师范大学 新型锝-99m标记的高级脂肪酸衍生物

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ZENG, HUAHUI ET AL.: "Preliminary studies of a novel cyclopentadienyl tricarbonyl technetium-99m fatty acid derivative for myocardical imaging.", J. LABEL COMPD. RADIOPHARM, vol. 56, 7 December 2012 (2012-12-07), pages 1 - 5 *
ZENG, HUAHUI ET AL.: "Synthesis and biological evaluation of fatty acids conjugates bearing cyclopentadienyl-donors incorporated [99mTc/Re(CO)3]+ for myocardical imaging.", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 72, 22 November 2013 (2013-11-22), pages 10 - 17 *

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