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GALLIUM-LABELED DRUG meetings

Foreign code F130007457
Posted date Jul 4, 2013
Country WIPO
International application number 2012JP065332
International publication number WO 2012173222
Date of international filing Jun 15, 2012
Date of international publication Dec 20, 2012
Priority data
  • P2011-135535 (Jun 17, 2011) JP
Title GALLIUM-LABELED DRUG meetings
Abstract Provided are a radioactive gallium-labeled drug, which comprises gallium 67 or gallium 68 and a complex having a complex structure formed from trisalicylaldiminomethyl-ethanol bonded to a compound that bonds with the target molecules, and which has increased uptake to the target site and stability; the radioactive gallium-labeled drug for diagnostic or therapeutic use; a ligand for preparation of the radioactive gallium-labeled drug; a kit containing, as individually packaged units, the drug containing the ligand and the drug containing the gallium 67 or gallium 68; and a method for producing the radioactive gallium-labeled drug.
Outline of related art and contending technology BACKGROUND ART
The agent is a radioactive label, a radioisotope label nuclides by pharmaceutical and, disease diagnosis and treatment of, for example is widely used for diagnosis and treatment of tumor are. Radioactive labeling agent can be integrated on the specific tissue or cell by, sensitive diagnosis and effective treatment can be performed, in addition, to reduce the side effects to normal tissues or cells can be. For example, tumor cells are transferred to the organs and tissues, are scattered even in such a case, the normal tissue or cell without affecting, effective diagnosis and treatment can be performed. Radioactive labeling agents in the diagnosis and treatment using, the selection of useful nuclides, the agent can be integrated in a specific tissue or cell have been made for drug design.
Gallium (Ga) constituting ratio of atomic number 31, belonging to the same first Group 13 indium. In various types of gallium Ga-67 nuclides (hereinafter,67 Gabe abbreviated) and Ga-68 (hereinafter,68 Gabe abbreviated) two radionuclides in the nuclear medicine diagnosis has a suitable nature.67 GaIs produced by the half-life time of the cyclotron 78 and the line γ-emitting radionuclide,67 Gacitrate (67 Ga-citrate) of diagnosis of the malignant tumor and inflammation as a single photonic radiation computed tomography (single photon emission computed tomography, hereinafter simply referred to as SPECT) are clinically used as agents for. On the other hand,68 Ga68 half and half life positron - emitting radionuclides, positron emission tomography (positron emission tomography, hereinafter, abbreviated as PET) are used in the diagnosis. In recent years, half-life of the germanium -68 2 70 (68 Ge) generator system using transient and by the development of equilibrium, can also be used for PET cyclotron nuclides not necessary as expected.
Protein or peptide bioactive molecules are generally, gallium does not have a stable binding site from, molecular targets for labeling bioactive molecules gallium, gallium coordination to the site of the binding site in a biologically active molecule having in the molecule and using the bifunctional chelator are made with the development of diagnostic agents. Actually, endocrine tumors express somatostatin receptor targeted DOTA-D-Phe1-Tyr3 - octreotide (DOTA-D-Phe1-Tyr3-octreotide, DOTA-TOC, non-patent document 1 and 2) of breast cancer and Her2 receptor affibody targeted DOTA (DOTA-affibody, non-patent document 3) and the like have been studied.
However, in the manufacture of pharmaceuticals is a radioactive label, a radioactive concentration of the metal radionuclide such as gallium is extremely low, for the purpose of radioactive labeling agents high radiochemical yield in order to obtain in a short time, a large excess of chelating agent, specifically 0.01-1 mm labeled using concentrations of the chelating agents is being performed. Therefore, such a radioactive labeling agents as it is administered to the living body, the chelating agent is not labeled with a radioactive labeling agents compete with the target site, results in loss of the radiolabeled agent is accumulated, as a result, it is thus the image of the target molecule. To cope with this problem, according to the study aimed at improving of specific radioactivity is performed, the ligand concentration is low and the reflectance is decreased marker in which case, the bifunctional chelator can be introduced into a plurality of labeled ratio is improved when the reduced affinity binding to a target molecule has been reported (non-patent document 4).
On the other hand, in the molecule of the binding site in the target molecule (sometimes referred to as a target molecule recognition element) a compound having a 2 molecule (divalent as compounds of the) molecule is a compound having 1 binding sites (monovalent as compounds) compared to the target molecule known to have high binding avidity and, this is because the polyvalent effect are widely used in the design of pharmaceutical agents (non-patent document 5-7). These findings suggest that, one target molecule recognition element to the metal atom with a monovalent ligand of 1:2 or 1:3 to make the complex, the stacking of a labeled to the target molecule can be expected to be improved.
In fact, the inventors of the present invention, as the metal radionuclide such as technetium - 99m (hereinafter,99m Tcbe abbreviated) to, the target molecule recognition element as Arg-Gly-Asp ligand having a binding penicillamine (hereinafter, sometimes referred to as RGD binding to penicillamine) used,99m Tcformed RGD and penicillamine and binding to the target molecule complex has high integration, and stable in vivo revealed that, the complex of radioactive labeling agents useful as shown to (Patent Document 1 and 2).
On the other hand, formed between the gallium and a ligand are 1:2 or 1:3 complexes of ligands of the in vivo and over and stably exist in the state in which a is not reported. In vivo, gallium complex and a ligand exhibits a behavior differing from that, to remove excess ligand and in the case where the stability is important. 2 Is a bidentate ligand forming complexes of gallium and deferiprone is 1:3, complex solution formed from the removal of excess of complex ligands have been reported collapse (non-patent document 8).
Scope of claims (In Japanese)請求の範囲 [請求項1]
標的分子に結合する化合物と結合させたトリサリチルアルジミノメチル エタノール[tri-salicylaldiminomethyl-ethanol、H 3(sal) 3TAMEol]と、ガリウム67またはガリウム68とから形成される錯体構造を有する錯体を含み、標的部位への集積性および安定性が増加した放射性ガリウム標識薬剤。

[請求項2]
標的分子に結合する化合物と結合させたH 3(sal) 3TAMEolが、配列表の配列番号1に示す環状ペンタペプチドと結合させたH 3(sal) 3TAMEolである請求項1に記載の放射性ガリウム標識薬剤。

[請求項3]
6-アミノヘキサノアート c(RGDfK)結合サリチルアルデヒドと、2,2’,2’’-トリ(アミノメチル)エタノール[2,2’,2’’-tri-(aminomethyl)-ethanol、TAMEol]と、ガリウム67またはガリウム68とをクエン酸溶液中で反応させることにより形成された錯体を含む、標的部位への集積性および安定性が増加した放射性ガリウム標識薬剤。

[請求項4]
診断用放射性標識薬剤である請求項1から3のいずれか1項に記載の放射性ガリウム標識薬剤。

[請求項5]
標的分子に結合する化合物と結合させたトリサリチルアルジミノメチル エタノール[tri-salicylaldiminomethyl-ethanol、H 3(sal) 3TAMEol]からなる、標的部位への集積性が増加した診断用放射性ガリウム標識薬剤の調製用配位子。

[請求項6]
標的分子に結合する化合物とサリチルアルデヒドとを有する化合物および2,2’,2’’-トリ(アミノメチル)エタノール[2,2’,2’’-tri-(aminomethyl)-ethanol、TAMEol]をインビトロで反応させることにより形成される化学構造を有する化合物からなる、標的部位への集積性が増加した放射性ガリウム標識薬剤の調製用配位子。

[請求項7]
標的分子に結合する化合物が配列表の配列番号1に示す環状ペンタペプチドである請求項5または6に記載の放射性ガリウム標識薬剤の調製用配位子。

[請求項8]
請求項5から7のいずれか1項に記載の放射性ガリウム標識薬剤の調製用配位子を含む薬剤と、ガリウム67またはガリウム68を含む薬剤とを、別々の包装単位として含んでなるキット。

[請求項9]
6-アミノヘキサノアート c(RGDfK)結合サリチルアルデヒドと、2,2’,2’’-トリ(アミノメチル)エタノール[2,2’,2’’-tri-(aminomethyl)-ethanol、TAMEol]と、ガリウム67またはガリウム68とを、別々の包装単位として含んでなるキット。

[請求項10]
標的分子に結合する化合物と結合させたトリサリチルアルジミノメチル エタノール[tri-salicylaldiminomethyl-ethanol、H 3(sal) 3TAMEol]を配位子として用い、ガリウム67またはガリウム68とインビトロで錯形成させることを含む放射性ガリウム標識薬剤の製造方法。

[請求項11]
標的分子に結合する化合物と結合させたH 3(sal) 3TAMEolが、配列表の配列番号1に示す環状ペンタペプチドと結合させたH 3(sal) 3TAMEolである請求項10に記載の放射性ガリウム標識薬剤の製造方法。

[請求項12]
6-アミノヘキサノアート-c(RGDfK)結合サリチルアルデヒドと、2,2’,2’’-トリ(アミノメチル)エタノール[2,2’,2’’-tri-(aminomethyl)-ethanol、TAMEol]と、ガリウム67またはガリウム68とをクエン酸溶液中で反応させることを含む、標的部位への集積性および安定性が増加した放射性ガリウム標識薬剤の製造方法。

  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • NATIONAL UNIVERSITY CORPORATION CHIBA UNIVERSITY
  • Inventor
  • ARANO, Yasushi
  • UEHARA, Tomoya
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT QA RO RS RU RW SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA RW SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
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