JP2008538545A - 橋頭標識化合物およびその使用方法 - Google Patents
橋頭標識化合物およびその使用方法 Download PDFInfo
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Abstract
Description
Y−L−BFR−X
式中、BFRは、置換されていることもある架橋縮合環系であり;Yは、標的化基であり(本発明では、「生物学的に活性な化合物」と呼ばれることもある);Lは、存在することもあり、YをBFRに結合させるリンカーであり;そして、Xはハロゲン(例えば、放射性ハロゲン)、放射性であることもあるCH2F官能基、または脱離基である。用語「脱離基」は、本明細書で使用するとき、入ってくる求核剤により置き換えられる基を表す。特に適する脱離基は、陰イオン性の基−OH−、−NH2 −、−F−、−Cl−、−Br−、−I−および−TosO−などの弱塩基である。
橋頭臭化およびヨウ化WAY誘導体の合成
橋頭WAY誘導体の合成をスキーム1に描いた通りに実施した(図10)。
購入できるか、または文献の方法(EW Della and J Tsanaktsidis (1985) Synthesis of bridgehead-bridgehead substituted bicycloalkanes Aust.J.Chem., 38, 1705-18)により合成されるジメチルジカルボキシレートから出発して、制御された鹸化 (R Priefer et al. (2002) Effective synthetic routes to cubylcarbinol derivatives Synthesis, 2671-2673)によりモノカルボン酸1を得た。酸化水銀(a,b,c)(NJ Bunce (1972) A mercury salt pathway for the degradation of carboxylic acids to alkyl halides using halogen and mercuric oxide J.Org.Chem. 37, 664-669)またはヨードベンゼンジアセテート(d)(R Priefer (2002) 上述)を使用するブロモ−またはヨード−脱カルボキシル化により、橋頭ハロゲン化化合物2を得た。
放射性標識[ 123 I]ヨードキュバン−WAYの製造
実施例1に従い製造したブロモキュバン−WAY前駆体2mgおよびCu(II)トリフラート0.1mgを、無水[123I]−ヨウ素を含むアセトニトリル100μlに溶解した。この混合物を密封容器中、30分間、140℃で加熱し、標識効率60−80%を達成した。
標識率に対する水の影響
[ 123 I]ヨードキュバン−WAYの標識率に対する水の影響を判定するために、10%まで漸増する量の水を実施例2に記載の通りに反応混合物に添加した。図8は、水が劇的に標識率を低下させたことを示す。
安定性試験
[123I]ヨードキュバン−WAYは、溶液中およびヒト血漿中で少なくとも24時間は完全に安定であると判明した。ヒト肝細胞において、アミド結合の遅い加水分解(t1/2=75分)が観察されたが、脱ヨウ素化は起こらなかった。これは、速い脱フッ素化速度と共に約15分間の半減期が見られたMPPFと対照的であった(図3参照)。
親和性試験
候補5−HT1A受容体トレーサーの相対的結合親和性は、[3H]8−OH−DPAT(Perkin Elmer, Boston, USA)を参照物質として使用して、競合結合アッセイで測定した(トレーサー毎にn=4)。ヒト組換えヒト5−HT1A受容体サブタイプを発現するHEK−293EBNA−細胞由来の膜懸濁物を、Perkin Elmer (Boston, USA)から入手した。元の懸濁液のタンパク質濃度は、36.8mg/mLであった。
結果を図6に示す。最高の親和性は、ヨード−キュビル−WAYについて見出された。
生体分布
非標識WAY−100635の事前投与によりHT1A受容体を遮断して、またはせずに、[123I]ヨードキュバン−WAY(15MBq)をオスの Wistar ラット(n=4)の尾静脈に注射した。注射後(p.i.)45分で、頸部切離によりラットを殺し、関心のある組織を取り出し、放射能を計測した。
モノクローナル抗体の標識化
メチル−4−ブロモキュバンカルボキシレート(1.5mg)、Cu(II)トリフレート(0.01mg)およびN,N−ジメチルピペラジン(0.1mg)を、nca[123I]ヨージド(750MBq)を含むアセトニトリル150μlの溶液に添加した。この混合物を、密封容器中、40分間、140℃で加熱した。[123I]メチル−4−ヨードキュバンカルボキシレート(620MBq、放射化学的収率83%)を前駆体からHPLCにより単離し、加水分解し、次いで、水溶性カルボジイミド(EDAC)を使用してテトラフルオロフェニルエステルに変換した。活性エステル(500MBq)をC−18SepPakにトラップし、そこからアセトニトリル0.5mLで溶出した。
[ 123 I]−(4−ヨードキュバン−1−イル)−アセトニトリルの合成
(4−ブロモキュバン−1−イル)−アセトニトリル(1.5mg)、Cu(II)トリフレート(0.01mg)およびN,N−ジメチルピペラジン(0.1mg)を、nca[123I]ヨージド(100MBq)を含むアセトニトリル150μlの溶液に添加した。この混合物を、密封容器中、40分間、140℃で加熱し、ほぼ定量的な(98%)収率の[123I]−(4−ヨードキュバン−1−イル)−アセトニトリルを得た。
Claims (21)
- 一般式:Y−L−BFR−X
[式中、BFRは、アダマンタン縮合環系以外の架橋縮合環系であり;
Yは、標的化基であり;
Lは、存在することもあり、YをBFRに結合させるためのリンカーであり;そして、
Xは、ハロゲン、18Fで標識されていることもあるCH2F基、または、標識用の官能基であり、ここで、XはBFRの橋頭原子に結合している]
を有する化合物。 - Xが123/124/131Iおよび76/77/82Brからなる群から選択される、請求項1に記載の化合物。
- Xが123Iである、請求項1に記載の化合物。
- Xが、−OH、−Brまたは−Iである、請求項1に記載の化合物。
- 一般式:Y−L−BFR−X
[式中、BFRは、架橋縮合環系であり;
Yは、標的化基であり;
Lは、存在することもあり、YをBFRに結合させるためのリンカーであり;そして、
Xは、BFRの橋頭原子に結合しており、
臭素およびヨウ素以外のハロゲン;
18Fで標識されていることもあるCH2F基;および
−CH2OSO2R、−OSO2R、−Sn(アルキル)3および−Pb(アルキル)3(ここで、Rは、−CH3、−CF3、−(C6H4)CH3および−(C6H4)NO2からなる群から選択される)
からなる群から選択される]
を有する化合物。 - BFRが、アダマンタン、ビシクロオクタン、ノルボルナンおよびキュバンからなる群から選択される、請求項5に記載の化合物。
- BFRが、ビシクロオクタン、ノルボルナンおよびキュバンからなる群から選択される、請求項1ないし請求項6のいずれかに記載の化合物。
- BFRがキュバンである、請求項1ないし請求項7のいずれかに記載の化合物。
- Xが非放射性である、請求項1および請求項5ないし請求項8のいずれかに記載の化合物。
- Xが放射性である、請求項1および請求項5ないし請求項8のいずれかに記載の化合物。
- Xが18Fまたは211Atである、請求項10に記載の化合物。
- Xが、−OSO2R、−Sn(アルキル)3および−Pb(アルキル)3からなる群から選択され、ここで、Rは、−CH3、−CF3、−(C6H4)CH3および−(C6H4)NO2からなる群から選択される、請求項1および請求項5ないし請求項8のいずれかに記載の化合物。
- Xが18Fで標識されていることもあるCH2F基である、請求項1および請求項5ないし請求項8のいずれかに記載の化合物。
- Xが−CH2OSO2Rであり、ここで、Rは、−CH3、−CF3、−(C6H4)CH3および−(C6H4)NO2からなる群から選択される、請求項1および請求項5ないし請求項8のいずれかに記載の化合物。
- Lが存在し、−O(CO)−、−NH(CO)−、−NH−、−O(CH2)n−、−NH(CH2)n−、−NH(CO)NH−および−NH(CS)NH−からなる群から選択される、請求項1ないし請求項14のいずれかに記載の化合物。
- BFRが、炭素原子のみからなる骨格を有する架橋縮合環系である、請求項1ないし請求項15のいずれかに記載の化合物。
- BFRが少なくとも1個のヘテロ原子を含む架橋縮合環系である、請求項1ないし請求項16のいずれかに記載の化合物。
- Yが、抗体、細胞に取り込まれる分子、および受容体または細胞に親和性を有する化学的または生物学的構造からなる群から選択される、請求項1ないし請求項17のいずれかに記載の化合物。
- 化合物が、WAY−100635の誘導体である、請求項1ないし請求項18のいずれかに記載の化合物。
- 医薬の標識化に使用するための化合物であって、一般式:M−BFR−X
[式中、BFRおよびXは、請求項1ないし請求項17のいずれかに記載の通りであり、Mは、BFRに直接結合しているか、またはリンカーにより間接的に結合しており、ここで、Mは、請求項1ないし請求項17のいずれかに記載のYの直接または間接的なBFRへの結合を可能にするものである]
を有する化合物。 - 医療的診断および医療的治療の少なくとも1つにおいて使用するための、請求項1ないし請求項19のいずれかに記載の化合物。
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JPN6011068840; Nuclear Medicine & Biology 25, 1998, pp.323-330 * |
JPN6011068842; Tetrahedron Letters 32(19), 1991, pp.2173-2176 * |
JPN6011068843; Nuclear Medicine & Biology 25, 1998, pp.769-776 * |
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JPN7011004752; J. Med. Chem. 37, 1994, pp.1406-1407 * |
JPN7011004753; J. Med. Chem. 42, 1999, pp.1576-1586 * |
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