WO2014164678A1 - Agents d'imagerie de la protéine de translocation, leurs méthodes de fabrication et leurs méthodes d'utilisation - Google Patents

Agents d'imagerie de la protéine de translocation, leurs méthodes de fabrication et leurs méthodes d'utilisation Download PDF

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Publication number
WO2014164678A1
WO2014164678A1 PCT/US2014/023195 US2014023195W WO2014164678A1 WO 2014164678 A1 WO2014164678 A1 WO 2014164678A1 US 2014023195 W US2014023195 W US 2014023195W WO 2014164678 A1 WO2014164678 A1 WO 2014164678A1
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Prior art keywords
alkyl
formula
radioligand
sec
subject
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PCT/US2014/023195
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English (en)
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Sabrina CASTELLANO
Federico DA SETTIMO PASSETTI
Claudia Martini
Giorgio STEFANCICH
Sabrina TALIANI
Victor W. Pike
Robert B. Innis
Yi Zhang
Sami S. ZOGHBI
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
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Publication of WO2014164678A1 publication Critical patent/WO2014164678A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates to radiolabeled 4-phenylquinazoline-2- carboxamides that are useful as radioligands for the detection of translocator protein 18 kDa (TSPO), which is a biomarker for neuroinflammation in neuropsychiatric and
  • PET positron emission tomography
  • TSPO also called the peripheral benzodiazepine receptor
  • TSPO is an 18 kDa mitochondrial protein expressed in inflammatory cells (microglia and reactive astrocytes) of the brain and is thus a potential biomarker for neuroinflammation. Activated microglia and increased levels of TSPO are associated with neuroinflammation.
  • PET imaging with radiotracers that bind specifically and selectively to TSPO has been used to quantify TSPO in vivo.
  • One such early radiotracer is, for example, [ 11 C]N-(5 , ec-butyl)-l-(2-chlorophenyl)-N- methylisoquinoline-3-carboxamide n C]PK 11195), which has the following structure.
  • the compound [ n C]PK 11195 often preferentially used as the single (R)- enantiomer, however, has a poor signal-to noise ratio and has high nonspecific binding.
  • the compound [ n C]PBR28 (N- ⁇ [2-(methyloxy) phenyl]methyl ⁇ -N-[4-(phenyloxy)-3- pyridinyl]acetamide) was designed as a leading second-generation TSPO radioligand and is shown below.
  • the compound [ n C]PBR28 has different affinities for TSPO in different patients, and the differential affinity is related to patient genotype. Specifically, polymorphisms in the TSPO gene lead to amino acid substitutions that result in differential binding affinity for different patients. This genotype sensitivity gives rise to patient populations for whom accurate PET imaging of TSPO protein is very difficult or impossible.
  • a radioligand of Formula 1, or a pharmaceutically acceptable salt thereof is disclosed:
  • X is O or S, R 1 is H or CI, R 2 is d to C 6 alkyl, R 3 is n CH 3 , R 4 is H or CI, and R is H;
  • X is O or S, R 1 is F, R 2 is d to C 6 alkyl, R 3 is n CH 3 , R 4 is H, and R is H or N0 2 ; or
  • X is O or S, R 1 is 18 F, R 2 is Ci to C 6 alkyl, R 3 is CH 3 , R 4 is H, and R is H or N0 2 .
  • radioligand of Formula 2 or a pharmaceutically acceptable salt thereof
  • Y is n C, X is O or S, R 1 is H or CI, R 2 is Ci to C 6 alkyl, R 3 is CH 3 , R 4 is H or CI, and R is H; or Y is n C, X is O or S, R 1 is F, R 2 is Ci to C 6 alkyl, R 3 is CH 3 , R 4 is H or CI, and R is H or N0 2 .
  • compositions comprising a radioligand of Formula 1 or 2 and a pharmaceutically acceptable carrier.
  • a method of detecting TSPO in a subject comprising administering to the subject a pharmaceutical composition comprising a detectable quantity of a radioligand of Formula 1, and detecting the compound in the subject.
  • a u C-methylating agent such as [ u C]methyl iodide or [ n C]methyl triflate, under conditions effective to form the compound of Formula 1,
  • X O or S
  • R 1 is H or CI
  • R 2 is Ci to C 6 alkyl
  • R 3 is n CH 3
  • R 4 is H or CI
  • R is H; or
  • X O or S
  • R 1 is F
  • R 2 is d to C 6 alkyl
  • R 3 is n CH 3
  • R 4 is H
  • R is H or N0 2 .
  • Figure 1 shows the displacement of [ H]PK 11195 with Compound la in leucocytes of HH (high affinity, open circles), HL (heterozygous, open diamonds), and LL (low affinity, open triangles).
  • Figure 2 shows mean time activity curves at baseline (dashed line) and pre- blocked with PK 11195 (solid line) for Compound la imaged using PET in monkey brains.
  • Figure 3 shows the Logan plot for Compound la to measure total distribution volume, VT, in a baseline scan in a representative brain region (prefrontal cortex).
  • Figure 4 shows Compound la levels in arterial plasma in baseline (dashed line) and pre-blocked (solid line) scans.
  • This invention is directed to novel radioligands, in particular radiolabeled 4- phenylquinazoline-2-carboxamides that bind TSPO, methods of making the radioligands, and their methods of use.
  • An important advantage of these new radioligands is different or lower genotype sensitivity than has been demonstrated for other TSPO radioligands. Thus, they can be used in all human subjects, regardless of genotype.
  • Alkyl as used herein means a monovalent group derived from a straight or branched chain saturated aliphatic hydrocarbon having the specified number of carbon atoms.
  • alkyl include methyl, ethyl, w-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, ie/t-butyl, w-pentyl, iso-pentyl, and w-hexyl.
  • (R)-alkyl as used herein means an alkyl group containing a chiral center having the (R)-configuration.
  • (5 , )-alkyl as used herein means an alkyl group containing a chiral center having the (S)-configuration.
  • (R ⁇ -alkyl) as used herein means a mixture of a compound including an (R)- alkyl group and its enantiomer containing an (5 , )-alkyl group in any ratio.
  • it can be a mixture of a compound including an (R)-alkyl group and its enantiomer containing an (5 , )-alkyl group in a 50:50 ratio (racemic mixture).
  • a novel radioligand i.e., a TSPO imaging agent
  • a TSPO imaging agent has the following Formula 1, or a pharmaceutically acceptable salt thereof:
  • X O or S, R 1 is H or CI, R 2 is Ci to C 6 alkyl, R 3 is n CH 3 , R 4 is H or CI and R is H;
  • X O or S, R 1 is F, R 2 is Ci to C 6 alkyl, R 3 is n CH 3 , R 4 is H, and R is H or N0 2 ; or
  • X O or S, R 1 is 18 F, R 2 is d to C 6 alkyl, R 3 is CH 3 , R 4 is H, and R is H or N0 2 .
  • X O or S
  • R 1 is H or CI
  • R 2 is (R)-Ci to C 6 alkyl, (5 Ci to C 6 alkyl or (R,S)-d to C 6 alkyl
  • R 3 is n CH 3
  • R 4 is H or CI and R is H;
  • X O or S
  • R 1 is F
  • R 2 is (R)-Ci to C 6 alkyl
  • R 3 is n CH 3
  • R 4 is H
  • R is H or N0 2 ;
  • X O or S
  • R 1 is 18 F
  • R 2 is (R)-Ci to C 6 alkyl, (5)-Ci to C 6 alkyl or (R,5)-Ci to C 6 alkyl
  • R 3 is CH 3
  • R 4 is H
  • R is H or N0 2 .
  • the radioligand of Formula 1 has Formula 4:
  • X O or S
  • R 1 is CI
  • R 2 is (R)-sec-butyl, (S)-sec-butyl or (R,S)-sec-buty ⁇
  • R 3 is U CH 3
  • R is H
  • X O or S
  • R 1 is F
  • R 2 is (R)-sec-butyl, (S)-sec-butyl or (R,S)-sec-buty ⁇
  • R 3 is n CH 3
  • R is H or N0 2 ; or
  • X O or S
  • R 1 is 18 F
  • R 2 is (R)-sec-butyl, (S)-sec-butyl or (R,S)-sec-buty ⁇
  • R 3 is CH 3
  • R is H or N0 2 .
  • Specific TSPO imaging agents are represented by Compounds Ia-c, Ila-c and Illa-c, or a pharmaceutically acceptable salt thereof:
  • variable R in compounds Ila-c and Illa-c are H or N0 2 .
  • radioligand of Formula 2 or a pharmaceutically acceptable salt thereof
  • Y is n C, X is O or S, R 1 is H or CI, R 2 is Ci to C 6 alkyl, R 3 is CH 3 , R 4 is H or CI, and R is H; or
  • Y is n C, X is O or S, R 1 is F, R 2 is d to C 6 alkyl, R 3 is CH 3 , R 4 is H or CI, and R is H or N0 2 .
  • Y is n C, X is O or S, R 1 is H or CI, R 2 is (R)-Ci to C 6 alkyl, (5 Ci to C 6 alkyl or (R,S)-d to C 6 alkyl, R 3 is CH 3 , R 4 is H or CI, and R is H; or
  • Y is n C, X is O or S, R 1 is F, R 2 is d to C 6 alkyl, (R)-Ci to C 6 alkyl, (5 Ci to C 6 alkyl or (R,S)-Ci to C 6 alkyl, R 3 is CH 3 , R 4 is H or CI, and R is H or N0 2 .
  • R is (R)-s'ec-butyl, (S)-sec-buty ⁇ , or (R,S)-sec butyl, for example,
  • Y is n C, X is O or S, R 1 is H or CI, R 2 is (R)-sec-butyl, (S)-sec-buty ⁇ , or (R,S)-sec butyl, R 3 is CH 3 , R 4 is H or CI, and R is H; or Y is n C, X is O or S, R 1 is F, R 2 is (R)-sec-butyl, (S)-sec-buty ⁇ , or (R,S)-sec butyl, R 3 is CH 3 , R 4 is H or CI, and R is H or N0 2 .
  • Y is n C
  • X is O
  • R 1 is H or CI
  • R 2 is (R)- seobutyl
  • R 3 is CH 3
  • R 4 is H or CI
  • R is H; or
  • Y is n C, X is O, R 1 is F, R 2 is (R)-sec-butyl, R 3 is CH 3 , R 4 is H or CI, and R is H or
  • Radioligands of Formula 4 may be prepared by a reaction of compounds of
  • radioligands of Formula 4 may be prepared by a n C-
  • Y is n C, X is O or S, R 1 is H or CI, R 4 is H or CI, R is H; and W is CI, Br, I,
  • radioligands of Formula 4 may be prepared by carbonylation of compounds represented by Formula 6 in the presence of an amine and u CO using a palladium(I) catalyst.
  • the compounds of Formula 1 or 2 can be used to detect the presence and location of TSPO in an organ or body area, such as the brain, of a subject.
  • the method comprises administration of a detectable quantity of a pharmaceutical composition containing a compound of Formula 1 or 2 or a pharmaceutically acceptable salt thereof, to a subject.
  • a "detectable quantity” means that the amount of the compound that is administered is sufficient to enable detection of binding of the compound to TSPO.
  • An “imaging effective quantity” means that the amount of the compound that is administered is sufficient to enable imaging of the compound bound to TSPO.
  • administration of the compound of Formula 1 or 2 is without regard to the TSPO genotype of the subject.
  • the compounds of Formula 1 or 2 are used in non-invasive nuclear medicine imaging techniques such as PET. Imaging is used to quantify TSPO in vivo.
  • imaging refers to a method that permits the detection of a labeled TSPO binding compound as described herein.
  • nuclear medicine imaging the radiation emitted from the organ or area being examined is measured and expressed either as total binding or as a ratio in which total binding in one tissue is normalized to (for example, divided by) the total binding in another tissue of the same subject during the same in vivo imaging procedure.
  • Total binding in vivo is defined as the entire signal detected in a tissue by an in vivo imaging technique without the need for correction by a second injection of an identical quantity of labeled compound along with a large excess of unlabeled, but otherwise chemically identical compound.
  • a "subject” is a mammal, specifically a human, and most specifically a human having or suspected of having neuroinflammation or a disease associated with peripheral inflammation.
  • the compounds of Formula 1 and 2 are labeled.
  • the type of detection is a major factor in selecting the label. For instance, labeling
  • C and F are particularly suitable for in vivo PET imaging with the compounds of Formula 1 and 2.
  • the type of instrument used will guide the selection of the radionuclide or stable isotope.
  • the radionuclide chosen should have a type of decay detectable by a given type of instrument.
  • Another consideration relates to the half-life of the radionuclide. The half-life should be long enough so that it is still detectable at the time of maximum uptake by the target, but short enough so that the host does not sustain deleterious radiation.
  • the radiolabeled compounds can be detected using nuclear medicine imaging wherein emitted radiation of the appropriate wavelength is detected.
  • imaging comprises PET imaging of the brain of a subject.
  • Neuroinflammatory processes are associated with neurodegenerative or neuropsychiatric disorders such as stroke, epilepsy, dementia, traumatic brain injury, anxiety, schizophrenia, bipolar disorder, autism, HIV infection of the brain, Alzheimer's disease, mild cognitive impairment, Huntington's disease, Parkinson's disease, multiple sclerosis, psychosis, and depression, for example.
  • depression includes major depressive disorder.
  • the labeled compounds of Formula 1 and 2 can be used for clinical investigation, diagnosis, and treatment.
  • the compounds of Formula 1 and 2 are used for imaging peripheral inflammation in a subject.
  • Peripheral inflammation is associated with disorders such as atherosclerosis and rheumatoid arthritis.
  • the dosage of the labeled TSPO binding compounds will vary depending on considerations such as age, condition, sex, and extent of disease in the patient, contraindications, if any, concomitant therapies and other variables, to be adjusted by a physician skilled in the art. Dosage can vary from 0.001 ⁇ g/kg to 10 ⁇ g/kg, specifically 0.01 ⁇ g/kg to 1.0 ⁇ g/kg.
  • Administration to the subject can be local or systemic and accomplished intravenously, intra-arterially, intrathecally (via the spinal fluid) or the like. Administration can also be intradermal or intracavitary, depending upon the body site under examination. After administration of the radioligand, the area of the subject under investigation is examined by imaging techniques such as PET imaging techniques. The exact protocol can vary depending upon factors specific to the subject, as noted above, and depending upon the body site under examination, method of administration and type of label used; the determination of specific procedures would be routine to the skilled artisan. Blood sampling may accompany imaging to allow for measurement of the arterial input function of the radioligand.
  • non-aqueous carriers examples include propylene glycol, polyethylene glycol, vegetable oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, saline solutions, parenteral vehicles such as sodium chloride, Ringer' s dextrose, etc.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • Preservatives include antimicrobials, anti-oxidants, chelating agents and inert gases. The pH and exact concentration of the various components of the pharmaceutical composition are adjusted according to routine skills in the art.
  • a pharmaceutical composition comprising a compound of Formula 1 or 2 is administered to subjects in whom neuroinflammation is suspected.
  • such subject is a human and includes, for instance, those who are at risk of developing neuropsychiatric or neurodegenerative disorders having a neuroinflammatory component.
  • the subject is being treated for a neuropsychiatric or neurodegenerative disorder and the method further comprises determining the effectiveness of the treatment for reducing or preventing neuroinflammation.
  • a method for producing a compound of Formula 1 comprises radiolabeling a compound having Formula 3 by
  • X O or S
  • R 1 is H or CI
  • R 2 is Ci to C 6 alkyl
  • R 3 is n CH 3
  • R 4 is H or CI
  • R is H; or
  • X O or S
  • R 1 is F
  • R 2 is d to C 6 alkyl
  • R 3 is n CH 3
  • R 4 is H
  • R is H or N0 2 .
  • X O or S
  • R 1 is H or CI
  • R 2 is (R)-Ci to C 6 alkyl, (5 Ci to C 6 alkyl or (R,5)-Ci to C 6 alkyl, R 3 is n CH 3 , R 4 is H or CI, and R is H; or
  • X O or S
  • R 1 is F
  • R 2 is (R)-Ci to C 6 alkyl, (5 Ci to C 6 alkyl or (R,S)-d to C 6 alkyl
  • R 3 is n CH 3
  • R 4 is H
  • R is H or N0 2 .
  • the u C-methylating agent is [ n C]methyl iodide.
  • contacting takes place in dimethyl sulfoxide, and/or the contacting takes place in the presence of potassium hydroxide. In an embodiment, contacting takes place at a temperature of about 80°C. In another embodiment, separating is carried out by a reverse-phase chromatography.
  • the compound of Formula 3 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe [0043]
  • R is H or N0 2 .
  • Compounds of Formula 2 having a carbon- 11 in the carbonyl or thiocarbonyl group may be labeled by the use of [ n C]carbon monoxide insertion reactions.
  • the radioligand was synthesized in a PLC controlled semirobotic Synthia apparatus (Synthia, Uppsala, Sweden), housed within the lead-shielded hot-cell.
  • the mixture was concentrated to dryness by rotary evaporation under reduced pressure and heat (80°C), formulated in sterile physiological saline (0.9% w/v; 10 mL) containing ethanol (10% v/v), and filtered through a sterile filter (0.2 ⁇ pore size, Millex-MP, 25 mm, Millipore) into a sterile, pyrogen-free dose vial.
  • Compound la was analyzed for
  • Example 5 In vivo imaging
  • a pair of baseline and pre-blocked TSPO PET scans of Compound la in two rhesus monkeys was performed. Decay- corrected brain region time-activity curves were recorded in both monkeys in baseline and TSPO blocked scans.
  • a more complete measurement of binding was performed by measuring total distribution volume, VT, using a metabolite-corrected arterial input function, i.e., Compound la levels in arterial plasma.
  • PK 11195 5 mg/kg was used as the TSPO blocking agent.
  • TSPO radioligands there are several advantages to the TSPO radioligands disclosed herein. First, subjects would no longer need to be screened for presence of the genotype, which takes time and for which the final results must be co-varied for HH and HL genotype. Second, 10% of the population that is homozygous LL for the low-affinity form would not need to be excluded from testing. That is, the compounds disclosed herein could be used in PET analysis without screening for genotype, and no subjects need be excluded.
  • “Pharmaceutically acceptable salts” includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, nontoxic, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • salts of the present compounds further include solvates of the compounds and of the compound salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH 2 ) n -COOH where n is 0-4, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phospho
  • carrier applied to pharmaceutical compositions of the disclosure refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • An excipient is an inactive ingredient useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use.

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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

L'invention concerne des 4-phénylquinazoline-2-carboxamides radiomarqués utilisés comme agents d'imagerie en tomographie par émission de positrons de la protéine de translocation (TSPO). L'invention concerne également des méthodes permettant de détecter la TSPO et la neuroinflammation en utilisant les composés. L'invention concerne par ailleurs des méthodes de radiomarquage de composés sélectionnés.
PCT/US2014/023195 2013-03-12 2014-03-11 Agents d'imagerie de la protéine de translocation, leurs méthodes de fabrication et leurs méthodes d'utilisation WO2014164678A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113387896A (zh) * 2021-06-17 2021-09-14 首都医科大学脑重大疾病研究中心(北京脑重大疾病研究院) 一种4-（2-氯芳基）喹唑啉-2-酰胺衍生物及其应用
WO2024095268A1 (fr) * 2022-11-02 2024-05-10 Technion Research & Development Foundation Limited Ligands de protéine de translocateur et maladies inflammatoires
WO2024095263A1 (fr) * 2022-10-31 2024-05-10 Yeda Research And Development Co. Ltd. Protocoles de conditionnement destinés à être utilisés avec des cellules veto cd8 + a memoire centrale anti-virales utilisées dans la transplantation de cellules souches haplo-identiques

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US4499094A (en) * 1982-04-27 1985-02-12 Pharmuka Laboratoires Derivatives of arene and hetero-arene carboxamides and their use as medicaments

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CHAUVEAU ET AL.: "Nuclear imaging of neuroinflammation: a comprehensive review of [11C]PK11195 challengers", EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, SPRINGER, BERLIN, DE, vol. 35, no. 12, 1 October 2008 (2008-10-01), pages 2304 - 2319, XP019654486, ISSN: 1619-7089, DOI: 10.1007/S00259-008-0908-9 *
RAHMAN ET AL.: "Synthesis of N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-[11C]carboxamide ([11C-carbonyl]PK11195) and some analogues using [11C]carbon monoxide and 1-(2-chlorophenyl)isoquinolin-3-yl triflate", J. CHEM. SOC., PERKIN TRANSACTIONS 1, no. 23, 26 November 2002 (2002-11-26), pages 2699 - 2703, XP055123415, ISSN: 1472-7781, DOI: 10.1039/b205838c *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113387896A (zh) * 2021-06-17 2021-09-14 首都医科大学脑重大疾病研究中心(北京脑重大疾病研究院) 一种4-（2-氯芳基）喹唑啉-2-酰胺衍生物及其应用
WO2024095263A1 (fr) * 2022-10-31 2024-05-10 Yeda Research And Development Co. Ltd. Protocoles de conditionnement destinés à être utilisés avec des cellules veto cd8 + a memoire centrale anti-virales utilisées dans la transplantation de cellules souches haplo-identiques
WO2024095268A1 (fr) * 2022-11-02 2024-05-10 Technion Research & Development Foundation Limited Ligands de protéine de translocateur et maladies inflammatoires

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