JP6030724B2 - Psma結合剤及びその使用 - Google Patents
Psma結合剤及びその使用 Download PDFInfo
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- JP6030724B2 JP6030724B2 JP2015174731A JP2015174731A JP6030724B2 JP 6030724 B2 JP6030724 B2 JP 6030724B2 JP 2015174731 A JP2015174731 A JP 2015174731A JP 2015174731 A JP2015174731 A JP 2015174731A JP 6030724 B2 JP6030724 B2 JP 6030724B2
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- compound
- radioisotope
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- iodine
- bromine
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Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- 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
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- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
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- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/61—Halogen atoms or nitro radicals
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
- C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nuclear Medicine (AREA)
Description
本願は、米国仮出願第61/085,462号(出願日:2008年8月1日)及び第61/111,791号(出願日:2008年11月6日)に基づく優先権を主張する(その全内容は参照により本願に組み込まれる)。本発明は、NIHグラント番号NIH U2492871、NIH R21CA114111、NIH CA111982及びDOD PC050825によって米国政府の支援を受けて行われた。米国政府は本発明に一定の権利を有する。
(I)
(式中、Zはテトラゾール又はCO2Qであり;各Qは独立して水素又は保護基から選択される)を有する化合物に関する。
を有するピリジン環であり、ここでXはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体、アスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)、B(OH)2、-NHNH2、-NHN=CHR3、-NHNH-CH2R3であり;nは1、2、3、4又は5であり;YはO、S、N(R')、C(O)、NR'C(O)、C(O)N(R')、OC(O)、C(O)O、NR'C(O)NR'、NR'C(S)NR'、NR'S(O)2、S(CH2)p、NR'(CH2)p、O(CH2)p、OC(O)CHR8NHC(O)、NHC(O)CHR8NHC(O)又は共有結合であり;ここでpは1、2又は3であり、R'はH又はC1-C6アルキルであり、R8はアルキル、アリール又はヘテロアリールであり、そのそれぞれは置換されていてもよく;R2はC1-C6アルキルであり;R3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、臭素、臭素の放射性同位体、アスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換されている。
であり、ここでX'はNHNH2、-NHN=CHR3及びNHNH-CH2R3からなる群から選択され;R3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体又はアスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換され;nは1、2、3、4又は5である。
であり、ここでGはO、NR'又は共有結合であり;R'はH又はC1-C6アルキルであり;pは1、2、3又は4であり、R7はNH2、N=CHR3、NH-CH2R3からなる群から選択され、ここでR3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体、アスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換されている。
本発明の実施形態は、下記、
(I)
(式中、Zはテトラゾール又はCO2Qであり、各Qは独立して水素又は保護基から選択される)に示す式Iの化合物を含む。
からなる群から選択されるピリジン環であり、ここでXはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体、アスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)、B(OH)2、-NHNH2、-NHN=CHR3、-NHNH-CH2R3であり;nは1、2、3、4又は5であり;YはO、S、N(R')、C(O)、NR'C(O)、C(O)N(R')、OC(O)、C(O)O、NR'C(O)NR'、NR'C(S)NR'、NR'S(O)2、S(CH2)p、NR'(CH2)p、O(CH2)p、OC(O)CHR8NHC(O)、NHC(O)CHR8NHC(O)又は共有結合であり;pは1、2又は3であり、R'はH又はC1-C6アルキルであり、R8はアルキル、アリール又はヘテロアリールであり、そのそれぞれは置換されていてもよく;R2はC1-C6アルキルであり;R3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体又はアスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換されているか;あるいはその薬学的に許容される塩である。
であり、ここでX'はNHNH2、-NHN=CHR3及びNHNH-CH2R3からなる群から選択され;R3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体又はアスタチンの放射性同位体;NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換され;R2はC1-C6アルキルであり;nは1、2、3、4又は5であるか;あるいはその薬学的に許容される塩である。
であり、ここでGはO、NR'又は共有結合であり;R'はH又はC1-C6アルキルであり;pは1、2、3又は4であり、R7はNH2、N=CHR3、NH-CH2R3からなる群から選択され、ここでR3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、臭素、臭素の放射性同位体又はアスタチンの放射性同位体;NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換され;R2はC1-C6アルキルであるか;あるいはその薬学的に許容される塩である。
からなる群から選択されるピリジン環であり、ここでXがフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体、アスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)、B(OH)2、-NHNH2、-NHN=CHR3、-NHNH-CH2R3である式Iの化合物を含む。特定の実施形態において、nは1である。各Qは独立して水素又は保護基から選択され;Zはテトラゾール又はCO2Qであり;YはO、S、N(R')、C(O)、NR'C(O)、C(O)N(R')、OC(O)、C(O)O、NR'C(O)NR'、NR'C(S)NR'、NR'S(O)2、S(CH2)p、NR'(CH2)p、O(CH2)p、OC(O)CHR8NHC(O)、NHC(O)CHR8NHC(O)又は共有結合であり;ここでpは1、2又は3であり、R'はH又はC1-C6アルキルであり、R8はアルキル、アリール又はヘテロアリールであり、そのそれぞれは置換されていてもよく;R2はC1-C6アルキルであり;R3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素臭素、臭素の放射性同位体又はアスタチンの放射性同位体;NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換されている。特定の実施形態において、R3はフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、臭素、臭素の放射性同位体又はアスタチンの放射性同位体で置換されたアリールである。
(式中、mは0ではない)を有する化合物を含む。Rは
からなる群から選択されるピリジン環であり、ここでXはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体、アスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)、B(OH)2、-NHNH2、-NHN=CHR3、又はNHNH-CH2R3である。R2はC1-C6アルキルであり;R3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素臭素、臭素の放射性同位体又はアスタチンの放射性同位体;NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換されている。特定の実施形態において、nは1である。他の特定の実施形態は、Xがフッ素、ヨウ素又はフッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体又はアスタチンの放射性同位体である化合物を含む。特定の実施形態において、R3はフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、臭素、臭素の放射性同位体又はアスタチンの放射性同位体で置換されたアリールである。特定の実施形態は、上記の構造(式中、ZはCO2Qであり、Qは水素であり、mは4である)を有する化合物を含む。
のp-メトキシベンジル(PMB)保護前駆体Lys-C(O)-Gluから製造できる。
(式中、mは0ではない)を有する化合物を含む。Rは
からなる群から選択されるピリジン環であり、ここでXはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体、アスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)、B(OH)2、-NHNH2、-NHN=CHR3、-NHNH-CH2R3である。R2はC1-C6アルキルであり;R3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素臭素、臭素の放射性同位体又はアスタチンの放射性同位体;NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換されている。特定の実施形態において、nは1である。他の特定の実施形態は、Xがフッ素、ヨウ素又はフッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体又はアスタチンの放射性同位体である化合物を含む。特定の実施形態において、R3はフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、臭素、臭素の放射性同位体又はアスタチンの放射性同位体で置換されたアリールである。特定の実施形態は、上記の構造(式中、ZはCO2Qであり、Qは水素であり、mは1、2又は3である)を有する化合物を含む。
(式中、X'は、-NHNH2、-NHN=CHR3、-NHNH-CH2R3からなる群から選択される)である式Iの化合物を含む。このような実施形態において、R3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、臭素、臭素の放射性同位体又はアスタチンの放射性同位体;NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)、B(OH)2で置換されている。R2はC1-C6アルキルであり;R3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素臭素、臭素の放射性同位体又はアスタチンの放射性同位体;NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換されている。特定の実施形態において、R3はフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、臭素、臭素の放射性同位体又はアスタチンの放射性同位体で置換されたアリールである。特定の実施形態は、nが1である化合物を含む。
a. スクシンイミジル4-[2-(tert-ブトキシカルボニル)ヒドラジノベンゾアート、トリエチルアミン、DMF、CH2Cl2;b. TFA、CH2Cl2;c. 4-フルオロベンズアルデヒド、50mM KH2PO4、CH3CN;d. 4-[18F]フルオロベンズアルデヒド、50mM KH2PO4
であり、ここでGがO、NR'又は共有結合であり、R'がH又はC1-C6アルキルであり、pが1、2、3又は4である式Iの化合物を含む。R7はNH2、N=CHR3及びNH-CH2R3から選択でき、ここでR3はアルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、臭素、臭素の放射性同位体、アスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)又はB(OH)2で置換され、ここでR2はC1-C6アルキルである。特定の実施形態において、R3はフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体又はアスタチンの放射性同位体で置換されたアリールである。特定の実施形態において、GはO又はNR'である。
a. N-tert-ブチルオキシカルボニル-O-(カルボキシメチル)ヒドロキシアミンヒドロキシスクシンイミジルエステル、トリエチルアミン、CH2Cl2;b. TFA、アニソール;c. p-フルオロベンズアルデヒド、トリエチルアミン、メタノール;d. p-[18F]フルオロベンズアルデヒド、トリエチルアミン、メタノール
a. スクシンイミジル6-(N'-tert-ブトキシカルボニル-ヒドラジノ)-ニコチナート、トリエチルアミン、CH2Cl2;b. TFA、CH2Cl2;c. 4-フルオロベンズアルデヒド、50mM KH2PO4、CH3CN;d. 4-[18F]フルオロベンズアルデヒド、50mM KH2PO4
[式中、R5は水素又はp-メトキシベンジルであり;R4は水素、
(式中、Aはフッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、臭素、臭素の放射性同位体、アスタチンの放射性同位体、Sn(R2)3、Si(R2)3又はHgClである)からなる群から選択される]を有する化合物を含む。さらなる実施形態は、上記の構造の化合物であって、放射性同位体を含むものを含む。特定の一実施形態は、下記の式
(式中、PMBはp-メトキシベンジルである)を有する化合物(PMB保護Lys-C(O)-Gluとしても知られる)を含む。他の特定の実施形態は、化合物2-[3-(5-アミノ-1-カルボキシ-ペンチル)-ウレイド]ペンタン二酸(Lys-C(O)-Gluとしても知られる)を含む。他の典型的な実施形態は、下記の化合物を含む。
典型的な放射性同位体含有化合物は下記の化合物を含む。
一般的手順。すべての試薬及び溶媒は、Sigma-Aldrich社(ウィスコンシン州ミルウォーキー)又はFisher Scientific社(ペンシルベニア州ピッツバーグ)のどちらかから購入した。PMB保護Lys-C(O)-Glu(化合物1)のトシラート塩は、報告された手順(19)に従って製造した。1H NMRスペクトルは、Varian Mercury 400mHzスペクトロメータ又はBruker Avance 400mHzスペクトロメータで得た。ESIマススペクトルは、API 15OEX(登録商標)、又はBruker Esquire 3000 plusシステムで得た。高分解能マススペクトル(HRMS)は、ノートルダム大学のMass Spectrometry FacilityにおいてJEOL JMS-AX505HA質量分析計で測定した。基準化合物のHPLC精製は、Waters 490E多波長UV/Vis検出器(マサチューセッツ州ミルフォード)を備えたWaters 625 LCシステムで行った。
2-{3-[5-(4-ヨード-ベンゾイルアミノ)-1-(4-メトキシ-ベンジルオキシカルボニル)-ペンチル]-ウレイド}ペンタン二酸ビス-(4-メトキシ-ベンジル)エステル(2)。1(0.126g,0.148mmol)のCH2Cl2(4mL)溶液にトリエチルアミン(0.1mL,0.712mmol)を加え、次いでN-ヒドロキシスクシンイミジル-4-ヨードベンゾアート(24)(0.073g,0.212mmol)を加えた。室温で2時間攪拌後、溶媒をロータリーエバポレーターで留去した。メタノール/塩化メチレン(5:95)を用いるシリカカラムで粗生成物を精製して2を0.127g(94%)得た。1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H), 7.17-7.26 (m, 6H), 6.77-6.86 (m, 7H), 5.37-5.46 (m, 2H), 4.93-5.09 (m, 6H), 4.32-4.40 (m, 2H), 3.76-3.77 (m, 9H), 3.30-3.33 (m, 2H), 2.30-2.36 (m, 2H), 2.07-2.12 (m, 1H), 1.84-1.92 (m, 1H), 1.70-1.79 (m, 1H), 1.49-1.57 (m, 3H), 1.25-1.33 (m, 2H). ESI-MS:C43H48IN3O11Na[M+Na]+として、計算値932.2;実測値932.7。
2-{3-[1-カルボキシ-5-(4-ヨード-ベンゾイルアミノ)-ペンチル]-ウレイド}ペンタン二酸(3)。0℃で2(0.117g,0.129mmol)にアニソール(3%)のTFA(15mL)溶液を加えた。混合物を室温で30分間攪拌し、次いでロータリーエバポレーターで濃縮した。粗生成物をHPLC(Econosil C18 10μ.、250x10mm、H2O/CH3CN/TFA(70/30/0.1)、4mL/分、3は11分で溶離する)で精製して、3を0.040g(57%)得た。1H NMR (400 MHz, D2O:CD3CN = 1:1 (v/v)) δ 7.79 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 4.08-4.16 (m, 2H), 3.26 (m, 2H), 2.35 (m, 2H), 2.00-2.03 (m, 1H), 1.72-1.84 (m, 2H), 1.52-1.62 (m, 3H), 1.34-1.36 (m, 2H). ESI-MS:C19H24IN3O8Na[M+Na]+として、計算値572.1;実測値572.0。FAB-HRMS:C19H25IN3O8[M+H]+として、計算値550.0686;実測値550.0648。
2-{3-[1-(4-メトキシ-ベンジルオキシカルボニル)-5-(4-トリブチルスタンナニル-ベンゾイルアミノ)-ペンチル]-ウレイド}ペンタン二酸ビス-(4-メトキシ-ベンジル)エステル(4)。1(0.120g,0.148mmol)のCH2Cl2(6mL)溶液にトリエチルアミン(0.1ml,0.712mmol)を加え、次いでN-ヒドロキシスクシンイミジル-4-トリブチルスタンニルベンゾアート(24)(0.075g,0.147mmol)を加えた。室温で2時間攪拌後、反応混合物をロータリーエバポレーターで濃縮した。メタノール/塩化メチレン(5:95)を用いるシリカカラムで粗生成物を精製し、4を0.130g(86%)得た。1H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 7.6 Hz, 2H), 7.18-7.24 (m, 6H), 6.80-6.85 (m, 6H), 6.47 (m, 1H), 5.44-5.47 (m, 2H), 4.95-5.09 (m, 6H), 4.41-4.45 (m, 2H), 3.76-3.77 (m, 9H), 3.32-3.38 (m, 2H), 2.35-2.37 (m, 2H), 2.08-2.16 (m, 1H), 1.90-1.94 (m, 1H), 1.70-1.79 (m, 1H), 1.45-1.64 (m, 9H), 1.24-1.30 (m, 8H), 1.01-1.06 (m, 6H), 0.85-0.87 (m, 9H). ESI-MS:C55H75N3O11SnNa[M+Na]+として、計算値1096.4;実測値1096.7。
2-{3-[5-(4-フルオロ-ベンゾイルアミノ)-1-(4-メトキシ-ベンジルオキシカルボニル)-ペンチル]-ウレイド}ペンタン二酸ビス-(4-メトキシ-ベンジル)エステル(5)。1(0.120g,0.164mmol)のCH2Cl2(4mL)溶液にトリエチルアミン(0.1mL,0.712mmol)を加え、次いでN-ヒドロキシスクシンイミジル-4-フルオロベンゾアート(22)(0.043g,0.181mmol)を加えた。室温で2時間攪拌後、ロータリーエバポレーターで溶媒を留去した。メタノール/塩化メチレン(5:95)を用いるシリカカラムで粗生成物を精製して、5を0.120g(91%)得た。 1H NMR (400 MHz, CDCl3) δ 7.78 (m, 2H), 7.16-7.24 (m, 6H), 7.01 (m, 2H), 6.80-6.85 (m, 7H), 5.51-5.64 (m, 2H), 4.93-5.09 (m, 6H), 4.34-4.40 (m, 2H), 3.75-3.77 (m, 9H), 3.28-3.34 (m, 2H), 2.26-2.38 (m, 2H), 2.04-2.15 (m, 1H), 1.82-1.91 (m, 1H), 1.68-1.74 (m, 1H), 1.44-1.57 (m, 3H), 1.25-1.33 (m, 2H). ESI-MS:C43H48FN3O11Na[M+Na]+として、計算値824.3;実測値824.7。
2-{3-[1-カルボキシ-5-(4-フルオロ-ベンゾイルアミノ)-ペンチル]-ウレイド}ペンタン二酸(6)。0℃で5(0.081g,0.1mmol)にアニソール(3%)のTFA(15mL)溶液を加えた。混合物を室温で20分間攪拌し、次いでロータリーエバポレーターで濃縮した。粗生成物をHPLC(Econosil C18 10μm、250x10mm、H2O/CH3CN/TFA(75/25/0.1)、4mL/分、精製した6は約9分で溶離する)で精製して、6を0.035g(79%)得た。1H NMR (400 MHz, D2O) δ 7.66-7.69 (m, 2H), 7.11-7.16 (m, 2H), 4.12-4.19 (m, 2H), 3.28-3.31 (m, 2H), 2.39-2.43 (m, 2H), 2.07-2.09 (m, 1H), 1.79-1.90 (m, 2H), 1.55-1.69 (m, 3H), 1.39-1.40 (m, 2H). ESI-MS:C19H24FN3O8Na[M+Na]+として、計算値464.1;実測値464.4。FAB-HRMS:C19H25FN3O8[M+H]+として、計算値442.1626;実測値442.1646。
2-(3-{1-(4-メトキシ-ベンジルオキシカルボニル)-5-[(5-トリブチルスタンナニル-ピリジン-3-カルボニル)-アミノ]-ペンチル}-ウレイド)ペンタン二酸ビス-(4-メトキシ-ベンジル)エステル(7)。1(0.120g,0.148mmol)のCH2Cl2(2mL)溶液にトリエチルアミン(0.1mL,0.712mmol)を加え、次いでN-ヒドロキシスクシンイミジル-5-(トリ-n-ブチルスタンニル)-3-ピリジンカルボキシラート(25)(0.075g,0.147mmol)を加えた。室温で30分間攪拌後、メタノール/塩化メチレン(5:95)を用いるシリカカラムで精製して、7を0.115g(76%)得た。1H NMR (400 MHz, CDCI3) δ 8.85 (s, 1H), 8.65 (s, 1H), 8.19 (s, 1H), 7.19-7.24 (m, 6H), 6.81-6.85 (m, 6H), 6.65 (m, 1H), 5.32-5.35 (m, 1H), 5.22-5.25 (m, 1H), 4.96-5.10 (m, 6H), 4.40-4.47 (m, 2H), 3.70-3.77 (m, 9H), 3.34 (m, 2H), 2.35-2.39 (m, 2H), 2.10-2.15 (m, 1H), 1.90-1.94 (m, 1H), 1.72-1.79 (m, 1H), 1.46-1.59 (m, 9H), 1.27-1.36 (m, 8H), 1.02-1.25 (m, 6H), 0.84-0.87 (m, 9H)。ESI-MS:C54H75IN4O11Sn[M+H]+として、計算値1075.4;実測値1075.5。
2-(3-{1-カルボキシ-5-[(5-ヨード-ピリジン-3-カルボニル)-アミノ]-ペンチル}-ウレイド)ペンタン二酸(8)。7(0.025g,0.023mmol)のメタノール(2mL)溶液に酢酸0.020mL及びヨウ化ナトリウム(0.017g,0.113mmol)を加え、次いでN-クロロスクシンイミド(0.025g,0.187mmol)を加えた。室温で20分後、溶媒を窒素気流下で除去した。次いで、TFAのCH2Cl2溶液(1:1、2mL)を残渣に加えた。室温で1時間後、HPLC(Econosphere C18 10μ.、250x10mm、H2O/CH3CN/TFA(85/15/0.1)、4mL/分、生成物ピークは10分で溶離する)で8(0.008g,62%)を単離した。 1H NMR (400 MHz, D2O) δ 9.00-9.15 (m, 3H), 4.18-4.24 (m, 2H), 3.40-3.41 (m, 2H), 2.45-2.49 (m, 2H), 2.12-2.13 (m, 1H), 1.85-1.97 (m, 2H), 1.64-1.73 (m, 3H), 1.44 (m, 2H). ESI-MS:C18H24IN4O8[M+H]+として、計算値551.1;実測値551.0。FAB-HRMS:C18H24IN4O8[M+H]+として、計算値551.0639;実測値551.0607。
2-{3-[1-カルボキシ-5-(4-[125I]ヨード-ベンゾイルアミノ)-ペンチル]-ウレイド}ペンタン二酸([125I]3)。対応するトリ-n-ブチルスタンニル前駆体4をヨード脱スタンニル化し次いで脱保護することによって[125I]3を製造した。4(1mg,0.932μmol)のメタノール0.1mL溶液に酢酸0.001mL及び[125I]NaIを加え、N-クロロスクシンイミド(0.25mg,0.187μmol)のメタノール0.025mL溶液を加えた。室温で20分間攪拌後、溶媒をN2気流下で除去した。次いで、残渣にアニソール(3%)のTFA溶液(0.1mL)を加えた。室温で5分後、HPLC(Econosil C18 10μ.、250x4.6mm、H2O/CH3CN/TFA(72/28/0.1)、1mL/分)によって[125I]3を単離した。Waters 510ポンプ、Waters 490E可変波長UV/Vis検出器(254nm)及びBioscan Flow Count PMT放射能検出器(ワシントンDC)を用いて、[125I]3の逆相ラジオHPLC精製を行った。この反応の収率は65〜80%であった(3回の異なる測定値)。比放射能は常に>700Ci/mmol(25.9GBq/μmol)であった。
N-ヒドロキシスクシンイミジル-4-[18F]フルオロベンゾアート[18F]SFB。N-ヒドロキシスクシンイミジル-4-[18F]ヨードベンゾアート([18F]SFB)を文献手順(23)で製造し、HPLC(Econosphere C18 10μ.、250x10mm、H2O/CH3CN/TFA(75/25/0.1)、5mL/分、生成物ピークは19で溶離する)で精製した。
2-(3-{1-カルボキシ-5-[(5-[125I]ヨード-ピリジン-3-カルボニル)-アミノ]-ペンチル}-ウレイド)-ペンタン二酸([125I]8)。対応するトリ-n-ブチルスタンニル前駆体7のヨード脱スタンニル化を用い、次いで脱保護して[125I]8を製造した。7(0.05mg,0.047μmol)のメタノール0.05mL溶液に酢酸0.002mL、[125I]NaIを加え、次いでN-クロロスクシンイミド(0.1mg,0.749μmol)のメタノール0.010mL溶液を加えた。室温で20分後、溶媒を窒素気流下で除去した。次いで、アニソール(3%)のTFA(0.1mL)溶液を残渣に加えた。室温で5分後、HPLC(Econosil C18 10μ.、250x4.6mm、H2O/CH3CN/TFA[85/15/0.1]、1mL/分)で[125I]8を単離した。Waters 510ポンプ、Waters 490E可変波長UV/Vis検出器(354nm)及びBioscan Flow Count PMT放射能検出器(ワシントンDC)を用いて[125I]8の逆相ラジオHPLC精製を行った。この反応の収率は59〜75%であった(3回の異なる測定値)。いずれの場合にも、比放射能は>2,000Ci/mmol(74.0GBq/μmol)であった。
2-(3-{1-カルボキシ-5-[2-(4-フルオロ-ベンジリデンアミノオキシ)-アセチルアミノ]-ペンチル}-ウレイド)ペンタン二酸(9)の合成。化合物1(0.062g,0.073mmol)のCH2Cl2(2mL)溶液にトリエチルアミン(0.045mL,0.320mmol)を加え、次いでN-tert-ブチルオキシカルボニル-O-(カルボキシメチル)ヒドロキシアミンヒドロキシスクシンイミジルエステル(0.025 g,0.087 mmol、Bioconjugate Chemistry 1993, 4, 515-20)を加えた。室温で30分間攪拌後、溶媒を留去した。メタノール/塩化メチレン(5:95)を用いるシリカカラムで粗生成物を精製し、化合物10を0.055g(89%)得た。1H NMR (400 MHz, CDC13) ( 7.98 (bs, 1H), 7.91 (s, 1H), 7.25-7.27 (m, 6H), 6.85-6.88 (m, 6H), 5.56-5.63 (m, 2H), 5.01-5.11 (m, 6H), 4.47-4.53 (m, 1H), 4.27-4.38 (m, 3H), 3.79 (m, 9H), 3.30-3.38 (m, 1H), 3.15-3.21 (m, 1H), 2.36-2.41 (m, 2H), 2.10-2.15 (m, 1H), 1.89-1.95 (m, 1H), 1.74-1.81 (m, 1H), 1.23-1.61 (m, 14H). ESI-MS:C43H57N4O14[M+H]+として、計算値853.4;実測値853.5。
室温で30分後、反応混合物をHPLC(Econosil C18 10μ、250x10mm、H2O/CH3CN/TFA(75/25/0.1)で精製して化合物9(0.002g,41%)を得た。1H NMR (400 MHz, D2O : CD3CN = 1:1) δ 8.26 (s, 1H), 7.56-7.80 (m, 2H), 7.10-7.14 (m, 2H), 4.53 (s, 2H), 4.13-4.17 (m, 1H), 3.96-4.00 (m, 1H), 3.16 (m, 2H), 2.37 (m, 2H), 2.10-2.16 (m, 1H), 1.80-1.88 (m, 2H), 1.65 (m, 1H), 1.54 (m, 1H), 1.42 (m, 1H), 1.28 (m, 1H). ESI-MS:C21H27F4O9Na[M+Na]+として、計算値521.2;実測値521.3。FAB-HRMS:C21H28FN4O9[M+H]+として、計算値499.1840;実測値499.1869。
2-(3-{1-カルボキシ-5-[2-(4-[18F]フルオロ-ベンジリデンアミノオキシ)-アセチルアミノ]-ペンチル}-ウレイド)ペンタン二酸([18F]9)の合成。文献手順(Nuclear Medicine and Biology 19 (1992) 275-281)を用いて4-[18F]フルオロベンズアルデヒドを合成し、HPLC(H2O/CH3CN/TFA70/30/0.1)で精製した。4-[18F]フルオロベンズアルデヒドのHPLC溶離液をH2Oで希釈し、C18 Sep Pakを通過させ、メタノール2mLで溶出した。化合物11(1mg)のメタノール(0.05mL)溶液に[18F]4-フルオロベンズアルデヒドのメタノール2mL溶液を加えた。室温で30分間攪拌し、反応混合物をHPLCで精製して化合物[18F]9を得た。放射化学的収率(減衰補正し、出発[18F]フルオリドに基づいて、n=2で)は6〜9%であった。最終化合物の比活性は350〜1300mCi/μmolであることが見いだされた。
2-[3-(1-カルボキシ-5-{4-[N'-(4-フルオロ-ベンジリデン)-ヒドラジノ]-ベンゾイルアミノ}-ペンチル)-ウレイド]ペンタン二酸(12)の合成。化合物1(0.030g,0.035mmol)のCH2Cl2(2mL)溶液にトリエチルアミン(0.020mL,0.142mmol)を加え、次いでスクシンイミジル4-[2-(tert-ブトキシカルボニル)ヒドラジノベンゾアート(0.020g,0.057mmol、Bioconjugate Chem. 1991, 2, 333-336)のDMF(0.2mL)溶液を加えた。室温で1時間攪拌後、溶媒を留去した。メタノール/塩化メチレン(5:95)を用いるシリカカラムで粗生成物を精製して、化合物13を0.025g(78%)得た。1H NMR (400 MHz, CDC13) δ 7.63 (d, J = 8.0 Hz, 2H), 7.19-7.23 (m, 6H), 6.81-6.85 (m, 6H), 6.68 (d, J = 8.8 Hz, 2H), 6.61 (s, 2H), 6.15 (bs, 1H) 5.68 (m, 2H), 4.95-5.07 (m, 6H), 4.34-4.45 (m, 2H), 3.74 (m, 9H), 3.25 (m, 2H), 2.31 (m, 2H), 2.10 (m, 1H), 1.84 (m, 1H), 1.19-1.74 (m, 14H). ESI-MS:C48H59N5O13Na[M+Na]+として、計算値936.4;実測値935.9。
2-[3-(1-カルボキシ-5-{4-[N'-(4-[18F]フルオロ-ベンジリデン)-ヒドラジノ]-ベンゾイルアミノ}-ペンチル)-ウレイド]ペンタン二酸(18F]12)の合成。既知の手順(Nuclear Medicine and Biology 33 (2006) 677-683)を用いて4-[18F]フルオロベンズアルデヒドを合成した。4-[18F]フルオロベンズアルデヒドの粗DMSO溶液に化合物14(1〜2mg)、50mM KH2PO4(0.2mL)を加えた。バイアルをふさぎ、90℃で15分間加熱した。次いで反応混合物をHPLC(Ecomosphere C18 10μ,250x10mm、H2O/CH3CN/TFA[70/30/0.1]、4mL/分)で精製した。放射化学的収率(減衰補正し、出発[18F]フルオリドに基づき、n=2で)は30〜55%であった。
化合物12は製造の直後に分解した。最終化合物の比活性は未測定である。
2-{3-[1-カルボキシ-5-({6-[N'-(4-フルオロ-ベンジリデン)-ヒドラジノ]-ピリジン-3-カルボニル}-アミノ)-ペンチル]-ウレイド}ペンタン二酸(15)の合成。化合物1(0.040g,0.047mmol)のCH2Cl2(2mL)溶液にトリエチルアミン(0.020mL,0.14mmol)を加え、次いでスクシンイミジル6-(N'-tert-ブトキシカルボニル-ヒドラジノ)-ニコチナート(0.020 g,0.057 mmol、Bioconjugate Chem. 1991, 2, 333-336)を加えた。室温で1時間攪拌後、溶媒を留去した。メタノール/塩化メチレン(10:90)を用いるシリカカラムで粗生成物精製して化合物16を0.032g(74%)得た。1H NMR (400 MHz, CDC13) δ 8.54 (s, 1H), 7.90 (m, 1H), 7.17-7.23 (m, 6H), 6.90-7.05 (m, 3H), 6.79-6.84 (m, 6H), 6.55 (d, J = 8.8 Hz, 2H), 5.79 (m, 2H), 4.94-5.07 (m, 6H), 4.38-4.45 (m, 2H), 3.74 (m, 9H), 3.26 (m, 2H), 2.33 (m, 2H), 2.07 (m, 1H), 1.85 (m, 1H), 1.68 (m, 1H), 1.18-1.55 (m, 13H). ESI-MS:C47H59N6O13[M+H]+として計算値915.4;実測値914.9。
2-{3-[1-カルボキシ-5-({6-[N'-(4-[18F]フルオロ-ベンジリデン)-ヒドラジノ]-ピリジン-3-カルボニル}-アミノ)-ペンチル]-ウレイド}ペンタン二酸([18F]15)の合成
in vitro結合
NAALADアーゼアッセイ。NAAGの加水分解は、本質的に前述の方法で行った(26)(27)。簡潔に言えば、NAALADアーゼ緩衝液(50mMトリス[pH7.4]及び0.5%トリトンX-100)中で、超音波処理によってLNCaP細胞抽出物を調製した。阻害薬の有り無しで、37℃で10分間細胞溶解物をインキュベートした。インキュベーションに続いて、放射性標識基質N-アセチル-L-アスパルチル-L-(3,4-3H)グルタマート(NEN Life Science Products社、マサチューセッツ州ボストン)を、37℃で10〜15分間、最終濃度が30nMとなるように加えた。等容量の氷冷した100mMリン酸ナトリウム及び2mM EDTAを添加して反応を停止させた。生成物をAG 1-X8ギ酸塩型樹脂(Bio-Rad Laboratories社、カリフォルニア州Hercules)陰イオン交換クロマトグラフィーによって分配し、1Mギ酸ナトリウムで溶出し、液体シンチレーション計数法で定量した。片対数プロットを用いて阻害曲線を作成し、酵素活性が50%阻害される濃度でIC50値を決定した。アッセイは3連で行い、親和性及び阻害様式を確認するために、全阻害試験を少なくとも2回行った。加水分解の直線相(すなわち、<全基質の20%切断)においてデータを採取した。チェン-プルソフ変換(28)を用いて酵素阻害定数(Ki値)を求めた。GraphPad Prism version 4.00 for Windows(登録商標) (GraphPad Software社、カリフォルニア州サンディエゴ)を用いてデータ分析を行った。
所定量の[3H]NAAG(30nM)に対して、各化合物の濃度を0.01nMから1000nMまで変化させた。
LNCaP細胞溶解物からNAALADアーゼ(PSMA)を調製した。生じた酵素切断産物である[3H]グルタマートの百分率をシンチレーション計数法によって測定し、研究中の化合物の対数濃度に対してプロットした。50%[3H]グルタマート生産(50%阻害)に対して得られたデータの線形回帰を求め、3に対して0.010nM、6に対して0.256nM、8に対して0.351nMのKi値を得た(表1)。この結果は、このクラスの他の化合物(30)に沿っている。これらの化合物を親和性に関する第2試験として蛍光ベースの阻害アッセイで評価したとき、3、6及び8のKi値は、それぞれ0.010、0.194及び0.557nMであった。
aNAALADアーゼ(放射定量)アッセイから得られた。b95%信頼区間。c蛍光ベースアッセイから得られた。
PSMA活性部位における阻害薬モデリング
タンパク質の構築。構造不規則性を補正し、アミノ酸残基の結合順序及び結合性を定めることができるDiscovery Studio 2.0(DS 2.0)で実行されるクリーンアッププロセスによって、2-PMPAとの複合体(PDB ID:2PVW)又は化合物3との複合体(PDB ID:3D7H)におけるGCPII結晶構造として、ドッキングスタディのためのGCPIIの3-D座標を求めた。タンパク質に作用するCHARMm力場及びドッキングスタディの結合部位は、受容体空洞部位の選択肢を用いて、自動化された方法によって得た。活性部位における2つの亜鉛イオン及び1つのクロリドイオンは、それぞれ+2及び1の形式電荷を有し、Zn2+及びCl-とタイプした。
細胞株及びマウスモデル:PC-3 PIP(PSMA+)及びPC-3 flu(PSMA-)細胞株はDr. Warren Heston(クリーブランド・クリニック)から入手したものであり、既述のように維持した(19)。すべての細胞は80〜90%コンフルエンスに達するまで増殖させ、次いでトリプシン処理し、ハンクス平衡塩溶液(HBSS、Sigma社、ミズーリ州セントルイス)に加えてマウスに移植した。
化合物[125I]3。異種移植SCIDマウスに、尾静脈を介して74Bq(2μCi)の[125I]3を注入した。注入後30分、60分、120分、300分、12時間、24時間及び48時間で、頸椎脱臼によってそれぞれ4匹のマウスを屠殺した。心臓、肺、肝臓、胃、膵臓、脾臓、脂肪組織、腎臓、筋肉、小腸、大腸、膀胱、PIP腫瘍及びflu腫瘍を直ちに摘出した。血液試料0.1mLもまた採取した。器官の重さをはかり、組織の放射能を自動γ線測定装置(1282 Compugamma CS、Pharmacia/LKB Nuclear社、メリーランド州ゲーサーズバーグ)で測定した。初回量の標準希釈試料との比較によって、組織1g当たりのパーセント注入量(%ID/g)を算出した。
全ての測定値を減衰補正した。
a.数値は%ID/g±SDである;ND=未測定;48時間目(n=3)を除いてn=4である。Int.=腸である。
b.Pip腫瘍:器官比は括弧内に示してある。
化合物[18F]6。以下の例外を除いて、[125I]3と同様に、ex vivo生体内分布を得た:マウスに3.7MBq(100[μCi)の[18F]6を注入し、取り込み時間は注入後30分、60分、120分及び300分であった。
表3 担腫瘍マウスにおける[18F]6のex vivo生体内分布a,b
a.数値は%ID/g±SD、n=4、int.=腸である。
b.Pip腫瘍:器官比は括弧内に示してある。
化合物[125I]8。PC-3 PIP及びPC-3 flu異種移植SCIDマウスに、尾静脈を介して74KBq(2μCi)の[125I]8を注入した。注入後30分、60分、240分、8時間及び24時間で、頸椎脱臼により、それぞれ4匹のマウスを屠殺した。直ちに心臓、肺、肝臓、胃、膵臓、脾臓、脂肪組織、腎臓、筋肉、小腸、大腸、膀胱、PIP腫瘍及びflu腫瘍を除去した。血液試料0.1mLもまた採取した。すべての器官の重さをはかり、自動γ線測定装置(1282 Compugamma CS、Pharmacia/LKB Nuclear社、メリーランド州ゲーサーズバーグ)で測定した。初回量の標準希釈試料との比較によって、%ID/gを算出した。全ての測定値を減衰補正した。
表4 担腫瘍マウスにおける[125I]8のex vivo生体内分布a,b
a.数値は%ID/g±SD、n=4、int.=腸である。
b.Pip腫瘍:器官比は括弧内に示してある。
化合物[125I]3。PC-3 PIP及びPC-3 flu異種移植片の両方を移植したスキッドマウス一匹に、37MBq(1mCi)の[125I]3の生理食塩液を静脈内に注入した。注入後4時間及び6時間で、マウスをイソフルランで麻酔し、1%イソフルランを含有する酸素下においた。マウスをX-SPECT(Gamma Medica社、カリフォルニア州ノースリッジ)のガントリー上に配置し、増分当たり45秒、6°の増分で360°回転する2つの低エネルギー高分解能ピンホールコリメータ(Gamma Medica社)を用いてスキャンした。Lunagemソフトウェア(Gamma Medica社、カリフォルニア州ノースリッジ)を用いて、すべてのガンマ画像を再構成した。SPECT収集後直ちに、600μA、50kVビームを用い、4.6cmの視野でCT(X-SPECT)でマウスをスキャンした。次いで、供給業者のソフトウェア(Gamma Medica社、カリフォルニア州ノースリッジ)を用いてSPECT及びCTデータを画像の位置合わせ処理を行い、AMIDE(http://amide.sourceforge.net/)を用いて表示した。逐次部分期待値最大化(OS-EM)アルゴリズムを用いてデータを再構成した。
[0138化合物[18F]6。in vivo PET-CT:PC-3 PIP及びPC-3 flu異種移植片を皮下に移植したスキッドマウス1匹を3%イソフルラン含有酸素を用いて麻酔を導入し、0.8L/分の流量の1.5%イソフルラン含有酸素で麻酔を維持し、GE eXplore Vista小動物PETスキャナ(GE Healthcare社、ウィスコンシン州Milwaukee、WI)のガントリー上にうつぶせに配置した。7.4MBq(200μCi)の[18F]6をマウスの静脈内に注入し、次いで以下のプロトコルを用いて画像収集を行った:準動的スキャン、すなわち3つのベッド位置で、全部で90分で得た一連の連続全身画像として画像を得た。各位置での滞留時間は5分であり、従って所定のベッド位置(又はマウス器官)は15分毎に再訪される。250〜700keVのエネルギーウィンドウを用いた。
FORE/2D-OSEM法(2反復、16サブセット)を用いて画像を再構成し、放射能低下、スキャナむだ時間及び散乱線に対する補正を含めた。
化合物[125I]8。LNCaP異種移植片を移植したスキッドマウス1匹に、37MBq(1mCi)の[125I]8の生理食塩液を静脈内に注入した。注入後4時間で、マウスをイソフルランで麻酔し、1%イソフルラン含有酸素下で麻酔を維持した。マウスをX-SPECT(Gamma Medica社、カリフォルニア州ノースリッジ)のガントリー上に配置し、増分当たり45秒、6°の増分で360°回転する2つの低エネルギー高分解能ピンホールコリメータ(Gamma Medica社)を用いてスキャンした。Lunagemソフトウェア(Gamma Medica社、カリフォルニア州ノースリッジ)を用いて、すべてのガンマ画像を再構成した。SPECT収集後直ちに、600μA、50kVビームを用い、4.6cmの視野でCT(X-SPECT)でマウスをスキャンした。次いで、供給業者のソフトウェア(Gamma Medica社、カリフォルニア州ノースリッジ)を用いてSPECT及びCTデータを画像の位置合わせ処理を行い、AMIDE(http://amide.sourceforge.net/)を用いて表示した。逐次部分期待値最大化(OS-EM)アルゴリズムを用いてデータを再構成した。
注入後5時間での化合物3(4-ヨードベンゾイル誘導体)及び注入後4時間での化合物8(3-ヨード-5-カルボキシル-ピリジル誘導体)に関する標的/非標的比を示す。標的/非標的比を下記の表5に示す。
表5
Claims (11)
- 構造
[式中、Zは、テトラゾール又はCO2Qであり;
各Qは、独立して水素又は保護基から選択され;かつ
mは、4であり、
Yは、NR'であり、
Rは、
であり、ここでGは、O、NR'又は共有結合であり;
R'は、H又はC1-C6アルキルであり;
pは、1、2、3又は4であり、
R7は、NH2、N=CHR3、NH-CH2R3からなる群から選択され、ここでR3は、アルキル、アルケニル、アルキニル、アリール又はヘテロアリールであり、そのそれぞれは、フッ素、ヨウ素、フッ素の放射性同位体、ヨウ素の放射性同位体、塩素、臭素、臭素の放射性同位体又はアスタチンの放射性同位体、NO2、NH2、N+(R2)3、Sn(R2)3、Si(R2)3、Hg(R2)、B(OH)2で置換され;
R2は、C1-C6アルキルである]を有する化合物。 - Zが、CO2Qである、請求項1記載の化合物。
- Qが、水素である、請求項1又は2記載の化合物。
- Gが、O又はNR'である、請求項1記載の化合物。
- Rが、放射性同位体を含む、請求項1〜4のいずれか1項に記載の化合物。
- 放射性同位体が、18F、123I、124I、125I、126I、131I、75Br、76Br、77Br、80Br、80mBr、82Br、83Br及び211Atからなる群から選択される、請求項5記載の化合物。
- 構造
を有する、請求項1記載の化合物。 - 請求項5〜7のいずれか1項に記載の化合物を含む、1以上の細胞、器官又は組織のイメージングに用いるための組成物。
- イメージングされる1以上の器官又は組織が、前立腺組織、腎組織、脳組織、血管組織又は腫瘍組織を含む、請求項8記載の組成物。
- 放射性同位体を含む、請求項1〜6のいずれか1項に記載の化合物を含む、腫瘍の治療のための医薬組成物。
- 請求項1〜7のいずれか1つに記載の化合物を含むキット。
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