JP6848015B2 - 放射性元素の標識方法、放射性標識化合物、及びそれを含む放射性元素標識キット - Google Patents
放射性元素の標識方法、放射性標識化合物、及びそれを含む放射性元素標識キット Download PDFInfo
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- JP6848015B2 JP6848015B2 JP2019117364A JP2019117364A JP6848015B2 JP 6848015 B2 JP6848015 B2 JP 6848015B2 JP 2019117364 A JP2019117364 A JP 2019117364A JP 2019117364 A JP2019117364 A JP 2019117364A JP 6848015 B2 JP6848015 B2 JP 6848015B2
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- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- XMBWDFGMSWQBCA-RNFDNDRNSA-M iodine-131(1-) Chemical compound [131I-] XMBWDFGMSWQBCA-RNFDNDRNSA-M 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
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- RAVVJKCSZXAIQP-UHFFFAOYSA-N methyl 5-bromopentanoate Chemical compound COC(=O)CCCCBr RAVVJKCSZXAIQP-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- ZLVYMPOQNJTFSG-QMMMGPOBSA-N monoiodotyrosine Chemical compound OC(=O)[C@@H](NI)CC1=CC=C(O)C=C1 ZLVYMPOQNJTFSG-QMMMGPOBSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
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- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 1
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- REDSKZBUUUQMSK-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC.CCCC[Sn](CCCC)CCCC REDSKZBUUUQMSK-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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Description
Z’−SH (Ia)
上記式(Ia)において、Z’は、上記式(I)のZで表される生体分子、蛍光染料又はナノ粒子化合物がチオール部分を含む場合、Zから−SH部分を除いた構造と同一であり、Zで表される生体分子、蛍光染料又はナノ粒子化合物がチオール部分を含まない場合には、Z’はZと同一である。
即ち、本発明において、チオール基を含むか、又はチオール基で置換された生体分子、蛍光染料又はナノ粒子混合物は、上記式(Ia)のような構造を有する。
上記Qにおいて、M、M’及びM’’は放射性元素である。
1.125I標識化合物の合成
(1)125I標識アルデヒド合成
125I標識アルデヒド[125I]5の合成のために、塩基性条件下で4−アミノブチルアルデヒドジエチルアセタールと4−ヨード安息香酸のカップリングによって非放射性類似体4−ヨード−N−(4−オキソブチル)ベンズアミド(5)を合成した後、次の段階を行った(スキーム1)。6の放射性ヨウ素化は、[125I]NaIとクロラミン(chloramines)−Tを酸化剤として用いて達成された(スキーム3)。放射性ヨウ素化反応は、ピロ亜硫酸ナトリウム(メタ重亜硫酸ナトリウム)水溶液を添加することにより終了させた。粗生成物のHPLC精製後、高い放射化学的収率(72±6%、n=5)で[125I]5を得た。比放射能(specific activity)は45GBq/μmolであり、化学純度は99%以上であった。粗混合物のHPLCクロマトグラムは、22.6分に主要生成物[125I]5を明確に示した(図1)。放射性標識(radio−labelling)反応は、様々な量の放射性(100μCi〜1mCi)を用いて行われたが、放射化学的結果は一貫していた。放射性ヨウ素化合物[125I]5は、6ヶ月以上冷蔵庫(4℃)内で安定していることが分かり、従来に用いられていた活性エステルベースの補欠分子族(prosthetic groups、Bolton−Hunter−reagent)とは異なり、加水分解されなかった。化合物[125I]5は、PBS、生理食塩水、及びマウス血清を含む様々な培地で、37℃で24時間以上安定していることが示され、これはradio−HPLC(図2)を用いて確認された。
試薬及び条件:(i)HBTU、DIPEA、4−アミノブチルアルデヒドジエチルアセタール、常温、2h、(ii)酸加水分解、(iii)Pd(Ph3P)4、ビス(トリブチルスズ)、1,4−ジオキサン、還流(reflux)、(iv)Cu+2、pH7.5、常温、2h、air
上記(1)に開示されているアリールジアミン化合物(4)は下記スキーム2により合成した。
試薬及び条件:(i)Zn/HCOOH、MeOH、1h、(ii)(Boc)2O、H2O、常温、2d、(iii)5−ブロモ吉草酸メチル、K2CO3、DMF、常温、24h、(iv)LiOH、Dioxane/H2O、常温、2h、(v)HBTU、DIPEA、常温、N−(2−アミノエチル)−マレイミドトリフルオロメチルアセテート、(vi)HCl、Et2O、2h
アルデヒドジアミンカップリング反応は、放射性ヨウ素化合物[125I]5及びジアミン基含有化合物4を用いて行われた。電子求引性(electron withdrawing)基(−OCH2−)が添加されたアリールジアミン環を選択してカップリング反応を促進させた。標的化合物[125I]7の放射合成前に、[125I]7のHPLC同定及び特性を表すために非放射性類似体7を合成した。化合物4及び5を触媒量の硫酸銅の存在下で常温及び大気下で攪拌することにより化合物7を合成した。放射性標識反応は、様々な濃度の5−(3,4−ジアミノフェノキシ)−N−(2−(2,5−ジオキソ−2,5−ジヒドロ−1H−ピロール−1−イル)エチル)ペンタンアミド4(5、25、50μM)と100μCiの[125I]5を室温で攪拌して行われた。上記反応は、radio−HPLCを用いて異なる時点でモニタリングされ、観察された放射化学的収率は表1にまとめられている。[125I]7の99%及び91%以上はそれぞれ50μM及び25μMの4を用いて常温で30分以内に得られた(エントリー2及び3)。また、[125I]5の80%以上が5μMの基質4を用いて[125I]7に30分以内に転換された(エントリー4)。50μMの前駆体4を用いたとき、5分での反応が遅かったが(エントリー1)、高い放射化学的収率がインキュベーション30分後に観察された。上記放射化学的収率及び反応動力学は、文献に開示されている多くのバイオコンジュゲート(bioconjugate)反応に匹敵することが分かった。
試薬及び条件:(i)[125I]NaI、クロラミン−T、DMSO、常温、10分、(ii)Cu+2、pH7.5、常温、air
下記スキーム4は、上記1で合成された本発明の放射性標識化合物[125I]5を活用して、癌標的(targeting)ペプチドとして生物学的研究及び臨床で非常に広く活用されているサイクリックRGDペプチドを放射性ヨウ素で標識する過程を示したものである。放射性元素標識されたcRGDペプチドは、αvβ3受容体に対する高い結合親和度及び選択性を有し、前臨床研究において転移性疾患及び急速に増殖する癌を検出するのに広く用いられる。SPECT又はPETに基づく腫瘍モデルの研究を行うために、放射性標識された多くのcRGDペプチドが開発された。本発明者らはまた、放射性元素標識戦略の効率性をテストするために、モデルペプチドとしてcRGDを選択した。標的化合物[125I]8の放射合成を下記スキーム4に示した。放射性標識反応は、異なる濃度のアリールジアミンを備えたcRGD8(5、25、50μM)と100μCiの[125I]5を触媒の存在下、室温で混合して行われた。放射性ヨウ素化反応は、radio−HPLCを用いてモニタリングされ、観察された放射化学的収率は上記表1にまとめて示した。[125I]8の99%以上が、30分以内にそして常温で(エントリー5)50μM8を用いて得られた。また、[125I]8の93%と69%はそれぞれ25μMと5μMの6で得られた。放射性標識反応では副反応がなく、放射性HPLCクロマトグラムにおいて放射性ヨウ素化された生成物が一つだけ観察された。
a 試薬及び条件:(i)[125I]5、Cu+2、常温、air
(1)125I標識HSA([125I]9)の製造
アリールジアミンアルキルアルデヒドカップリング反応の放射性同位元素標識効率を決定するために、[125I]5は、ヒト血清アルブミンタンパク質9を含有するアリールジアミンで処理された。ヒト血清アルブミンタンパク質は、薬物伝達体として使用できる上、薬物が血液中に留まる時間を増加させて血液循環時間を向上させる。本実験では、マレイミド−システイン−34コンジュゲーションを適用した。
a 試薬及び条件:(i)PBS、常温、pH7.5、10h、(ii)[125I]5、Cu+2、air、常温
上記(1)と類似の工程によって、下記スキーム6のように99mTc標識HSAを製造した。
上記(1)と類似の工程によって、下記スキーム7のように68Ga、111In、及び89Zr標識HSAを製造した。
3.(1)で合成された本発明の125I標識HSA([125I]9)の生体内臓器分布及び体内挙動の評価をICR雄性マウスを用いて行った。各マウスに1μCiの放射標識製品を静脈注射し、体内分布データを注射後0.5、3、6、24、及び36時間に収集した。初期放射能濃度(24.07±1.28%ID/g)が血液プール(pool)から発見された。活性水準は、注射後24時間(8.32±0.72%ID/g)及び36時間(6.73±0.48%ID/g)(図3)でも非常に高かった。このような観察は、[125I]9が長い血液循環時間を有し、[125I]9と結合した後に迅速に除去される薬物の血液半減期を増加させるのに用いられることができることを示唆する。図3を参考すると、脾臓、肝臓、小腸、大腸、肺、心臓、及び胃腸など、他の器官における放射能吸収(uptake)は初期時点では有意に高かったが、時間の経過とともに減少した。腎臓吸収量がやや高いということは、尿を介した標識化合物の除去を示唆する。甲状腺における放射能蓄積は、概ね生体内での脱ヨウ素化を示し、I.V注射後24時間及び36時間には5.20±1.61%ID/g及び4.86±1.01%ID/gであった。
Claims (18)
- 前記ジアミノフェニル化合物を提供する段階は、チオール部分(Thiol moiety)を含む下記式(Ia)の化合物を提供する段階と、
下記式(Ia)の化合物と下記式(Ib)の化合物とを反応させて前記式(I)の化合物を獲得する段階と、を含む、請求項1に記載の放射性元素の標識方法。
Z’−SH (Ia)
(前記式(Ia)において、Z’は、前記式(I)のZで表される生体分子、蛍光染料又はナノ粒子化合物がチオール部分を含む場合、Zから−SH部分を除いた構造と同一であり、Zで表される生体分子、蛍光染料又はナノ粒子化合物がチオール部分を含まない場合には、Z’はZと同一である。)
- 前記式(Ia)の化合物と前記式(Ib)の化合物の反応は、Cu+2系触媒下、常温、大気条件で行われるものである、請求項2に記載の放射性元素の標識方法。
- 前記チオール部分(Thiol moiety)を含む前記式(Ia)の化合物を提供する段階は、チオール部分(Thiol moiety)を含んでいない生体分子、蛍光染料又はナノ粒子化合物Z’にチオール部分をさらに置換して前記式(Ia)の化合物を提供する段階を含む、請求項2又は請求項3に記載の放射性元素の標識方法。
- 前記生体分子は、ペプチド、アフィボディ(affibody)、抗体、及びオリゴヌクレオチドからなる群から選択される少なくとも一つである、請求項1から請求項4のいずれか一項に記載の放射性元素の標識方法。
- 前記ナノ粒子は、金属ナノ粒子、合成高分子ナノ粒子、及び生体高分子ナノ粒子からなる群から選択される少なくとも一つである、請求項1から請求項5のいずれか一項に記載の放射性元素の標識方法。
- 前記金属ナノ粒子は、金(Au)、白金(Pt)、パラジウム(Pd)、銀(Ag)、及び銅(Cu)からなる群から選択されるいずれか一つの金属、又はコバルト(Co)、マンガン(Mn)、鉄(Fe)、ニッケル(Ni)、ガドリニウム(Gd)、モリブデン(Mo)、亜鉛(Zn)、及びクロム(Cr)からなる群から選択されるいずれか一つの金属酸化物ナノ粒子である、請求項1から請求項6のいずれか一項に記載の放射性元素の標識方法。
- 前記蛍光染料は、シアニン(cyanine)、フルオレセイン(fluorescein)、及びローダミン(rhodamine)系から選択される少なくとも一つである、請求項1から請求項7のいずれか一項に記載の放射性元素の標識方法。
- 前記放射性元素は、I、F、Tc、Re、Ga、In、Zr、Y、Ho、Sm、及びLuからなるグループから選択される、請求項1から請求項8のいずれか一項に記載の放射性元素の標識方法。
- 放射性元素MはI又はFであり、M’はTc又はReであり、M’’はGa、In、Y、及びZrからなるグループから選択される元素である、請求項1から請求項9のいずれか一項に記載の放射性元素の標識方法。
- 前記生体分子は、ペプチド、アフィボディ(affibody)、抗体、及びオリゴヌクレオチドからなる群から選択される少なくとも一つであり、前記ナノ粒子は、金属ナノ粒子、合成高分子ナノ粒子、及び生体高分子ナノ粒子からなる群から選択される少なくとも一つであり、前記金属ナノ粒子は、金(Au)、白金(Pt)、パラジウム(Pd)、銀(Ag)、及び銅(Cu)からなる群から選択されるいずれか一つの金属、又はコバルト(Co)、マンガン(Mn)、鉄(Fe)、ニッケル(Ni)、ガドリニウム(Gd)、モリブデン(Mo)、亜鉛(Zn)、及びクロム(Cr)からなる群から選択されるいずれか一つの金属酸化物であり、そして、前記蛍光染料は、シアニン(cyanine)、フルオレセイン(fluorescein)、及びローダミン(rhodamine)系から選択される少なくとも一つである、請求項12に記載の放射性元素標識用キット。
- 前記放射性元素は、I、F、Tc、Re、Ga、In、Zr、Y、Ho、Sm、及びLuからなるグループから選択される、請求項12又は請求項13に記載の放射性元素標識用キット。
- 請求項16に記載の前記式(IV)で表される放射性元素が標識された生体分子、蛍光染料又はナノ粒子化合物を有効成分として含む、医療診断用組成物。
- 前記医療診断は、単一光子放射断層撮影(SPECT)、陽電子放射断層撮影(PET)、マイクロ−PET、コンピュータ断層撮影(CT)、磁気共鳴画像(MRI)又は放射線診断機器の標的画像による診断である、請求項17に記載の医療診断用組成物。
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