JP2015030671A - Tracer for pet diagnosis for malignant tumor - Google Patents
Tracer for pet diagnosis for malignant tumor Download PDFInfo
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- JP2015030671A JP2015030671A JP2013159132A JP2013159132A JP2015030671A JP 2015030671 A JP2015030671 A JP 2015030671A JP 2013159132 A JP2013159132 A JP 2013159132A JP 2013159132 A JP2013159132 A JP 2013159132A JP 2015030671 A JP2015030671 A JP 2015030671A
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Abstract
Description
本発明は、陽電子放出同位体を用いた悪性腫瘍のPET診断用トレーサーに関する。 The present invention relates to a PET diagnostic tracer for malignant tumors using a positron emitting isotope.
腫瘍に対するポルフィリン類の親和性はよく知られており、比較的長い三重項寿命を有するポルフィリン化合物は、光線力学療法(PDT)を用いた悪性腫瘍の治療に使用されている。
他方、ポルフィリン化合物は、腫瘍の治療のみならず、腫瘍を可視化して腫瘍を検出又は診断するツールとして利用することが可能である。ポルフィリンはそれ自身が赤色に蛍光する物質であることから光線力学診断(PDD)として用いられてもいる。しかしこの診断では、多量の薬剤が必要となりこの薬剤によって正常部位に損傷（光細胞毒性）を与えてしまう。一方、陽電子放射断層撮影(Positron Emission Tomography：PET)に用いる薬剤濃度は光細胞毒性の起こらない低濃度で診断することから、ポルフィリンに由来する副作用がほぼないという利点がある。
The affinity of porphyrins for tumors is well known, and porphyrin compounds having a relatively long triplet lifetime are used for the treatment of malignant tumors using photodynamic therapy (PDT).
On the other hand, porphyrin compounds can be used not only for tumor therapy but also as a tool for visualizing tumors to detect or diagnose tumors. Porphyrin is also used as a photodynamic diagnosis (PDD) because it is a substance that fluoresces red. However, this diagnosis requires a large amount of drug, which damages the normal site (photocytotoxicity). On the other hand, since the drug concentration used for positron emission tomography (PET) is diagnosed at a low concentration that does not cause photocytotoxicity, there is an advantage that there is almost no side effect derived from porphyrin.
18F-FDG（フルオロデオキシグルコース）は、主にPETに使用されている診断薬である。しかし、18F-FDGは、糖を必要としない部位や通常でも糖代謝が高い部位の診断には適用することができないため、脳腫瘍や胃癌の診断をすることが困難である。また、18Fは半減期(t1/2 = 1.83時間)が短いため、使用しにくいという問題がある。 18 F-FDG (fluorodeoxyglucose) is a diagnostic agent mainly used for PET. However, 18 F-FDG is difficult to diagnose brain tumors and gastric cancers because it cannot be applied to the diagnosis of sites that do not require sugar or that normally have high glucose metabolism. Further, 18 F has a short half -life (t 1/2 = 1.83 hours), so that it is difficult to use.
また、胃癌や脳腫瘍に特異的に集積するポルフィリン誘導体(Photochlor)に124I核（t1/2= 4.13日)を導入したSingle-photon emission computed tomography (SPECT)用薬剤として、124I-Photochlor誘導体が開発された。マウス大腸癌(Colon26)腫瘍を移植したBALB/cマウスに対し、この化合物を用いた生体動態が報告されている（文献名：Suresh K. Pandey, J.Med. Chem. 2005, 48, 6286-6296（非特許文献１））。この化合物はPDT薬剤の誘導体であるが、放射核種を導入するための前駆体合成が特別に必要となり、放射核種の導入にも時間がかかる。このため、123I核(t1/2= 13時間)が使えず、半減期の長い124I核を用いたSPECT診断しかできない。この124I-Photochlor誘導体は腫瘍に集積するものの集積までの時間が遅く（48時間かかる）、また遊離したヨウ素が甲状腺に集まるという問題がある。 In addition, as a drug for single-photon emission computed tomography (SPECT) in which 124 I nucleus (t 1/2 = 4.13 days) is introduced into porphyrin derivative (Photochlor) that accumulates specifically in gastric cancer and brain tumor, 124 I-Photochlor derivative Was developed. Biological dynamics using this compound have been reported for BALB / c mice transplanted with mouse colon cancer (Colon 26) tumor (literature name: Suresh K. Pandey, J. Med. Chem. 2005, 48, 6286- 6296 (Non-Patent Document 1)). Although this compound is a derivative of a PDT drug, it requires special synthesis of a precursor for introducing the radionuclide, and it takes time to introduce the radionuclide. For this reason, 123 I nuclei (t 1/2 = 13 hours) cannot be used, and only SPECT diagnosis using 124 I nuclei with a long half-life is possible. Although this 124 I-Photochlor derivative accumulates in the tumor, it takes a long time to accumulate (it takes 48 hours), and free iodine collects in the thyroid gland.
本発明は、悪性腫瘍のPET診断用トレーサーを提供することを目的とする。 An object of the present invention is to provide a PET tracer for malignant tumors.
本発明者は、上記課題を解決するため鋭意研究を行った結果、 ポルフィリン化合物に陽電子亜鉛などの陽電子放出金属同位体を錯体化した物質を作製し、これを用いてPET診断を行うことにより従来よりも効果的に腫瘍を検出し得ることを見出し、本発明を完成するに至った。 As a result of diligent research to solve the above-mentioned problems, the present inventor has produced a substance obtained by complexing a porphyrin compound with a positron emitting metal isotope such as positron zinc and conducting PET diagnosis using this substance. The present inventors have found that a tumor can be detected more effectively than the present invention, and have completed the present invention.
すなわち、本発明は、次の［1］〜［12］に記載の発明を提供するものである。
［1］次式(I)：
R3、R6、R9及びR12は、それぞれ独立して、水素原子、任意に置換されてもよいC1-10アルキル、任意に置換されてもよいC2-10アルケニル、任意に置換されてもよいC2-10アルキニル、任意に置換されてもよいC6-14アリール、任意に置換されてもよいC7-20アリールアルキル、又は任意に置換されてもよい5〜14員ヘテロアリールを表し、ここで、置換基は、C1-6アルキル、C6-14アリール、C7-20アリールアルキル、OR20及びCOOR20（R20は前記と同様である。）、酸素原子、窒素原子、炭素原子又は硫黄原子が結合してもよい糖、ハロゲン原子、並びに次式：
で示される基からなる群から選ばれる少なくとも１つであり、
各置換基は、アミノ酸、葉酸、抗体、次式：
で示される基、アジ化物又はこれらの組み合わせを含む基でさらに置換されてもよく、
Mは、[64Cu]、[52Mn] 、[52Fe]、[99mTc]、[111In]、[68Ga]及び[62Zn]から選択される陽電子放出核種であり、
で示されるポルフィリン化合物を含む、腫瘍のPET診断用トレーサー。
［2］R1、R2、R4、R5、R7、R8、R10及びR11は、それぞれ独立して、水素原子、又は任意に置換されてもよいC1-10アルキルを表し、ここで、置換基は、アミド結合を有する基、並びにOR20及びCOOR20（R20は、水素原子、C1-6アルキル、C2-6アルケニル又はC2-6アルキニルを表す。）からなる群から選ばれる少なくとも１つである、［1］に記載のトレーサー。
［3］R3、R6、R9及びR12は、それぞれ独立して、水素原子、又は任意に置換されてもよいC6-14アリールを表し、ここで、置換基は、OR20及びCOOR20（R20は前記と同様である。）、酸素原子、窒素原子、炭素原子又は硫黄原子が結合してもよい糖、ハロゲン原子、並びに次式：
で示される基からなる群から選ばれる少なくとも１つであり、
各置換基は、葉酸、次式：
で示される基、アジ化物又はこれらの組み合わせを含む基でさらに置換されてもよい、
［1］または［2］に記載のトレーサー。
［4］ R1、R2、R4、R5、R7、R8、R10及びR11は、水素原子を表し、
R3、R6、R9及びR12は、それぞれ独立して、任意に置換されてもよいC6-14アリールを表し、ここで、置換基は、酸素原子、窒素原子、炭素原子又は硫黄原子が結合してもよい糖、ハロゲン原子、並びに次式：
で示される基からなる群から選ばれる少なくとも１つである、［1］〜［3］のいずれか１項に記載のトレーサー。
［5］アミド結合を有する基が、-CONHCH2CH2NHCOCH2CH2COOR40（R40は次式：
で示される基を表す。）で示される基である、［1］〜［3］のいずれか１項に記載のトレーサー。
［6］Mが[62Zn] である［1］〜［5］のいずれか１項に記載のトレーサー。
［7］ハロゲン原子がFである［1］〜［6］のいずれか１項に記載のトレーサー。
［8］ポルフィリン化合物が、次式(II)、(III)、(IV)、(V)、(VI)、(VII)及び(VIII)のいずれかで示されるものである［1］に記載のトレーサー。
［9］次式(IX)で示されるポルフィリン化合物を含む、腫瘍のPET診断用トレーサー。
［10］次式(IV)で示されるポルフィリン化合物。
［11］ 次式(VII)で示されるポルフィリン化合物。
［12］次式(I')：
R3、R6、R9及びR12は、それぞれ独立して、水素原子、任意に置換されてもよいC1-10アルキル、任意に置換されてもよいC2-10アルケニル、任意に置換されてもよいC2-10アルキニル、任意に置換されてもよいC6-14アリール、任意に置換されてもよいC7-20アリールアルキル、又は任意に置換されてもよい5〜14員ヘテロアリールを表し、ここで、置換基は、C1-6アルキル、C6-14アリール、C7-20アリールアルキル、OR20及びCOOR20（R20は前記と同様である。）、酸素原子、窒素原子、炭素原子又は硫黄原子が結合してもよい糖、ハロゲン原子、並びに次式：
で示される基からなる群から選ばれる少なくとも１つであり、
各置換基は、アミノ酸、葉酸、抗体、次式：
で示される基、アジ化物又はこれらの組み合わせを含む基でさらに置換されてもよく、
で示されるポルフィリン化合物に、[64Cu]、[52Mn]、[52Fe]、[99mTc]、[111In]、[68Ga]及び[62Zn]から選択される陽電子放出核種を導入することを特徴とする、次式(I)：
で示される化合物の製造方法。
That is, the present invention provides the inventions described in the following [1] to [12].
[1] The following formula (I):
R 3 , R 6 , R 9 and R 12 are each independently a hydrogen atom, optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted Optionally substituted C 2-10 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-20 arylalkyl, or optionally substituted 5-14 membered hetero Represents aryl, wherein the substituents are C 1-6 alkyl, C 6-14 aryl, C 7-20 arylalkyl, OR 20 and COOR 20 (R 20 is as defined above), an oxygen atom, A sugar, halogen atom to which a nitrogen atom, carbon atom or sulfur atom may be bonded, as well as the following formula:
At least one selected from the group consisting of groups represented by:
Each substituent is an amino acid, folic acid, antibody,
May be further substituted with a group including a group represented by
M is a positron emitting nuclide selected from [ 64 Cu], [ 52 Mn], [ 52 Fe], [ 99m Tc], [ 111 In], [ 68 Ga] and [ 62 Zn],
A tracer for PET diagnosis of tumor, comprising a porphyrin compound represented by
[2] R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 10 and R 11 are each independently a hydrogen atom or an optionally substituted C 1-10 alkyl. Wherein the substituent is a group having an amide bond, and OR 20 and COOR 20 (R 20 represents a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl). The tracer according to [1], which is at least one selected from the group consisting of:
[3] R 3 , R 6 , R 9 and R 12 each independently represent a hydrogen atom or an optionally substituted C 6-14 aryl, wherein the substituent is OR 20 and COOR 20 (R 20 is as defined above), an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom to which a carbon atom or sulfur atom may be bonded, a halogen atom, and the following formula:
At least one selected from the group consisting of groups represented by:
Each substituent is folic acid, the following formula:
Which may be further substituted with a group including
The tracer according to [1] or [2].
[4] R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 10 and R 11 represent a hydrogen atom,
R 3 , R 6 , R 9 and R 12 each independently represent optionally substituted C 6-14 aryl, wherein the substituent is an oxygen atom, nitrogen atom, carbon atom or sulfur A sugar to which an atom may be bonded, a halogen atom, and the following formula:
The tracer according to any one of [1] to [3], which is at least one selected from the group consisting of groups represented by:
[5] A group having an amide bond is represented by —CONHCH 2 CH 2 NHCOCH 2 CH 2 COOR 40 (R 40 represents the following formula:
Represents a group represented by The tracer according to any one of [1] to [3], which is a group represented by:
[6] The tracer according to any one of [1] to [5], wherein M is [ 62 Zn].
[7] The tracer according to any one of [1] to [6], wherein the halogen atom is F.
[8] The porphyrin compound is represented by any one of the following formulas (II), (III), (IV), (V), (VI), (VII) and (VIII) Tracer.
[9] A PET diagnostic tracer comprising a porphyrin compound represented by the following formula (IX):
[10] A porphyrin compound represented by the following formula (IV):
[11] A porphyrin compound represented by the following formula (VII):
[12] Formula (I ′):
R 3 , R 6 , R 9 and R 12 are each independently a hydrogen atom, optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted Optionally substituted C 2-10 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-20 arylalkyl, or optionally substituted 5-14 membered hetero Represents aryl, wherein the substituents are C 1-6 alkyl, C 6-14 aryl, C 7-20 arylalkyl, OR 20 and COOR 20 (R 20 is as defined above), an oxygen atom, A sugar, halogen atom to which a nitrogen atom, carbon atom or sulfur atom may be bonded, as well as the following formula:
At least one selected from the group consisting of groups represented by:
Each substituent is an amino acid, folic acid, antibody,
May be further substituted with a group including a group represented by
A positron emitting nuclide selected from [ 64 Cu], [ 52 Mn], [ 52 Fe], [ 99m Tc], [ 111 In], [ 68 Ga] and [ 62 Zn] is introduced into the porphyrin compound represented by The following formula (I):
The manufacturing method of the compound shown by these.
本発明により、ポルフィリン化合物に陽電子放出金属同位体を錯体化した化合物が提供される。本発明の化合物は、悪性腫瘍のPET診断用トレーサーとして利用できる点で極めて有用である。 According to the present invention, a compound obtained by complexing a porphyrin compound with a positron emitting metal isotope is provided. The compound of the present invention is extremely useful in that it can be used as a tracer for PET diagnosis of malignant tumors.
以下、本発明を詳細に説明する。
本発明は、ポルフィリン化合物に陽電子放出金属同位体を錯体化した化合物であり、悪性腫瘍のPET(Positron Emission Tomography)の診断用トレーサーとして利用することができるものである。
Hereinafter, the present invention will be described in detail.
The present invention is a compound obtained by complexing a porphyrin compound with a positron emitting metal isotope, and can be used as a diagnostic tracer for malignant tumor PET (Positron Emission Tomography).
本発明者は、ポルフィリンの腫瘍特異的集積性に着目し、陽電子放出金属同位体を用いてポルフィリンに錯体形成し、さらに必要に応じて錯体を糖鎖やエチレングリコール等で修飾した。この修飾された錯体は、腫瘍特異的に集積することからPET用造影剤として利用することができる。 The inventor paid attention to the tumor-specific accumulation property of porphyrin, formed a complex with porphyrin using a positron emitting metal isotope, and further modified the complex with a sugar chain, ethylene glycol or the like as necessary. Since this modified complex accumulates in a tumor-specific manner, it can be used as a PET contrast agent.
腫瘍細胞は、ブドウ糖の細胞膜輸送が正常細胞に比較すると亢進しているため、増殖することができる。フルオロデオキシグルコース（FDG）は、ブドウ糖の類似物質であり、ブドウ糖と同様に細胞に取り込まれてFDG6リン酸に変化する。その後、解糖系で代謝されずに細胞内に蓄積される。FDGにおけるF18（フッ素18）（18F-FDGという）はγ線を発生するので、PETでは、そのγ線を検出して画像化させる。従って、PET造影においては、患者に18F-FDGを投与してその集積を診断する。しかし、脳や胃などの正常でも糖利用の多い臓器では、腫瘍を検出することが困難であった。 Tumor cells can proliferate because glucose cell membrane transport is enhanced compared to normal cells. Fluorodeoxyglucose (FDG) is a similar substance to glucose and, like glucose, is taken up by cells and converted to FDG6 phosphate. Thereafter, it is accumulated in the cell without being metabolized in the glycolytic system. Since F18 (fluorine 18) (referred to as 18 F-FDG) in FDG generates γ rays, PET detects and images the γ rays. Therefore, in PET imaging, 18 F-FDG is administered to a patient to diagnose its accumulation. However, it has been difficult to detect tumors in normal organs such as the brain and stomach, which have high sugar utilization.
そこで本発明者は、脳などの糖利用の多い臓器でも腫瘍を検出することを可能とするべく鋭意研究を行った結果、62Zn等の陽イオン放出金属同位体を用いて錯体を形成させることにより高感度に腫瘍を検出することを見出した。
本発明は、金属が導入されていないポルフィリン化合物に陽電子放出核種を導入することを特徴とするポルフィリン誘導体の迅速合成法を提供する。また、本発明は、合成されたポルフィリン誘導体がin vitro及びin vivoにおいて特異的に胃癌に集積するという知見に基づき、新規PET診断用トレーサーを提供する。
Therefore, as a result of intensive studies to enable detection of tumors even in organs with high sugar utilization such as brain, the present inventor has formed a complex using a cation-emitting metal isotope such as 62 Zn. Has been found to detect tumors with high sensitivity.
The present invention provides a rapid synthesis method of a porphyrin derivative characterized by introducing a positron emitting nuclide into a porphyrin compound into which no metal is introduced. The present invention also provides a novel PET diagnostic tracer based on the finding that the synthesized porphyrin derivative specifically accumulates in gastric cancer in vitro and in vivo.
本発明において使用されるポルフィリン化合物は次式(I)に示されるものである。
式(I)：
R3、R6、R9及びR12は、それぞれ独立して、水素原子、任意に置換されてもよいC1-10アルキル、任意に置換されてもよいC2-10アルケニル、任意に置換されてもよいC2-10アルキニル、任意に置換されてもよいC6-14アリール、任意に置換されてもよいC7-20アリールアルキル、又は任意に置換されてもよい5〜14員ヘテロアリールを表し、ここで、置換基は、C1-6アルキル、C6-14アリール、C7-20アリールアルキル、OR20及びCOOR20（R20は前記と同様である。）、酸素原子、窒素原子、炭素原子又は硫黄原子が結合してもよい糖、ハロゲン原子、並びに次式：
で示される基からなる群から選ばれる少なくとも１つであり、
各置換基は、アミノ酸、葉酸、抗体、次式：
で示される基、アジ化物又はこれらの組み合わせを含む基でさらに置換されてもよく、
Mは、[64Cu]、[52Mn] 、[52Fe]、[99mTc]、[111In]、[68Ga]及び[62Zn]から選択される陽電子放出核種であり、
Formula (I):
R 3 , R 6 , R 9 and R 12 are each independently a hydrogen atom, optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted Optionally substituted C 2-10 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-20 arylalkyl, or optionally substituted 5-14 membered hetero Represents aryl, wherein the substituents are C 1-6 alkyl, C 6-14 aryl, C 7-20 arylalkyl, OR 20 and COOR 20 (R 20 is as defined above), an oxygen atom, A sugar, halogen atom to which a nitrogen atom, carbon atom or sulfur atom may be bonded, as well as the following formula:
At least one selected from the group consisting of groups represented by:
Each substituent is an amino acid, folic acid, antibody,
May be further substituted with a group including a group represented by
M is a positron emitting nuclide selected from [ 64 Cu], [ 52 Mn], [ 52 Fe], [ 99m Tc], [ 111 In], [ 68 Ga] and [ 62 Zn],
本発明において、「C1-10アルキル」、「C1-6アルキル」とは、炭素数がそれぞれ1〜10個、1〜6個の直鎖状又は分枝鎖状のアルキル基を意味する。このようなアルキル基としては、例えば、メチル基、エチル基、1-プロピル基、2-プロピル基、2-メチル-1-プロピル基（i-ブチル基）、2-メチル-2-プロピル基（t-ブチル基）、1-ブチル基、2-ブチル基、1-ペンチル基、ヘキシル基、1-メチルブチル基、2-メチルブチル基、3-メチルブチル基などが挙げられ、好ましくは、メチル基、エチル基、1-プロピル基、2-プロピル基などである。 In the present invention, “C 1-10 alkyl” and “C 1-6 alkyl” mean a linear or branched alkyl group having 1 to 10 and 1 to 6 carbon atoms, respectively. . Examples of such an alkyl group include a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, a 2-methyl-1-propyl group (i-butyl group), a 2-methyl-2-propyl group ( t-butyl group), 1-butyl group, 2-butyl group, 1-pentyl group, hexyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, etc., preferably methyl group, ethyl Group, 1-propyl group, 2-propyl group and the like.
「C2-10アルケニル」、「C2-6アルケニル」とは、炭素数がそれぞれ1〜10個、2〜6個の直鎖状又は分枝鎖状のアルケニル基を意味する。このようなアルケニル基としては、例えばエテニル基（ビニル基）、1-プロペニル基、2-プロペニル基（アリル基）、1-ブテニル基、2-ブテニル基、3-ブテニル基、ペンテニル基などが挙げられる。
「C2-10アルキニル」、「C2-6アルキニル」とは、炭素数がそれぞれ2〜10個、2〜6個の直鎖状又は分枝鎖状のアルキニル基を意味する。このようなアルキニル基としては、例えばエチニル基、1-プロピニル基、2-プロピニル基、1-ブチニル基、2-ブチニル基、3-ブチニル基、ペンチニル基などが挙げられる。
“C 2-10 alkenyl” and “C 2-6 alkenyl” mean straight or branched alkenyl groups having 1 to 10 and 2 to 6 carbon atoms, respectively. Examples of such alkenyl groups include ethenyl group (vinyl group), 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, pentenyl group and the like. It is done.
“C 2-10 alkynyl” and “C 2-6 alkynyl” mean linear or branched alkynyl groups having 2 to 10 and 2 to 6 carbon atoms, respectively. Examples of such alkynyl groups include ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, pentynyl group and the like.
「C6-14アリール」とは、炭素数が6〜14個の芳香族炭化水素基を意味し、例えばフェニル基、1-ナフチル基、2-ナフチル基、インデニル基などが挙げられ、好ましくはフェニル基である。
「C7-20アリールアルキル」は、C7〜C12アリールアルキル基であることが好ましい。アリールアルキル基の例としては、例えばベンジル、フェネチル、ジフェニルメチル、トリフェニルメチル、1-ナフチルメチル、2-ナフチルメチル、2,2-ジフェニルエチル、3-フェニルプロピル、4-フェニルブチル、5-フェニルペンチル等を挙げることができる。
「5〜14員ヘテロアリール」とは、環を構成する原子数が5〜14個であり、その原子中に1〜5個のヘテロ原子（窒素原子、酸素原子又は硫黄原子）を含有する芳香族基を意味する。このようなヘテロアリール基としては、例えばフリル基、チエニル基、ピロリル基、イミダゾリル基、トリアゾリル基、テトラゾリル基、チアゾリル基、ピラゾリル基、オキサゾリル基、イソオキサゾリル基、イソチアゾリル基、フラザニル基、チアジアゾリル基、オキサジアゾリル基、ピリジル基、ピラジニル基、ピリダジニル基、ピリミジニル基などが挙げられる。
“C 6-14 aryl” means an aromatic hydrocarbon group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, and an indenyl group, preferably It is a phenyl group.
“C 7-20 arylalkyl” is preferably a C 7 -C 12 arylalkyl group. Examples of arylalkyl groups include benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenyl A pentyl etc. can be mentioned.
“5- to 14-membered heteroaryl” is a fragrance having 5 to 14 atoms constituting a ring and containing 1 to 5 heteroatoms (nitrogen, oxygen or sulfur atoms) in the atoms. Means a group. Such heteroaryl groups include, for example, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, furazanyl, thiadiazolyl, oxadiazolyl Group, pyridyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group and the like.
本発明において、「アミド結合」とは、カルボニル基と窒素との結合を意味し、「アミド結合を有する基」としては、例えば-CONHCH2CH2NHCOCH2CH2COOR40（R40は次式：
で示される基を表す。）で示される基が挙げられる。
In the present invention, the “amide bond” means a bond between a carbonyl group and nitrogen, and the “group having an amide bond” includes, for example, —CONHCH 2 CH 2 NHCOCH 2 CH 2 COOR 40 (R 40 is represented by the following formula: :
Represents a group represented by ).
本発明において、「ハロゲン原子」とは、フッ素原子(F)、塩素原子(Cl)、臭素原子(Br)又はヨウ素原子(I)を意味し、好ましくはFである。
本発明において、「糖」としては、グルコース、ガラクトース、アラビノース、キシロース、フコース、グルコサミン、ガラクトサミンなどが挙げられ、酸素原子、窒素原子、炭素原子又は硫黄原子が結合した糖も含まれる。中でも、硫黄原子（チオール基）が結合したグルコースが好ましい。
In the present invention, the “halogen atom” means a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br) or an iodine atom (I), preferably F.
In the present invention, examples of the “sugar” include glucose, galactose, arabinose, xylose, fucose, glucosamine, galactosamine and the like, and sugars to which an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom is bonded are also included. Among these, glucose to which a sulfur atom (thiol group) is bonded is preferable.
また、本発明において、「アミノ酸」は、同一分子内にカルボキシル基とアミノ基を有する化合物をいうが、プロリン、ヒドロキシプロリン等のイミノ酸もアミノ酸に含まれる。アミノ酸としては、グリシン、アラニン、バリン、ロイシン、イソロイシン、セリン、トレオニン、アスパラギン酸、グルタミン酸、アスパラギン、グルタミン、リシン、ヒドロキシリシン、アルギニン、システイン、シスチン、メチオニン、フェニルアラニン、チロシン、トリプトファン、ヒスチジン、プロリン、4-ヒドロキシプロリンなどが挙げられる。 In the present invention, “amino acid” refers to a compound having a carboxyl group and an amino group in the same molecule, but imino acids such as proline and hydroxyproline are also included in the amino acid. As amino acids, glycine, alanine, valine, leucine, isoleucine, serine, threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, hydroxylysine, arginine, cysteine, cystine, methionine, phenylalanine, tyrosine, tryptophan, histidine, proline, 4-hydroxyproline and the like can be mentioned.
「葉酸」は、プテロイルグルタミン酸であり、下記式：
「抗体」としては、モノクロナール抗体などが挙げられる。
「アジ化物」は、-N3原子団を持つ化合物であり、アジドともいう。本発明においては、アジ化物には、トリアゾリル基なども含まれる。
“Folic acid” is pteroylglutamic acid, which has the following formula:
“Antibodies” include monoclonal antibodies.
“Azide” is a compound having a —N 3 atomic group, and is also referred to as azide. In the present invention, the azide includes a triazolyl group and the like.
また、式(I)において、
本発明の好ましい態様において、 R1、R2、R4、R5、R7、R8、R10及びR11は、それぞれ独立して、水素原子、又は任意に置換されてもよいC1-10アルキルを表し、ここで、置換基は、アミド結合を有する基、並びにOR20及びCOOR20（R20は、水素原子、C1-6アルキル、C2-6アルケニル又はC2-6アルキニルを表す。）からなる群から選ばれる少なくとも１つである。 In a preferred embodiment of the present invention, R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 10 and R 11 are each independently a hydrogen atom or optionally substituted C 1. Represents a -10 alkyl group, wherein the substituent includes a group having an amide bond, and OR 20 and COOR 20 (R 20 represents a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl). At least one selected from the group consisting of:
また、本発明の好ましい態様において、R3、R6、R9及びR12は、それぞれ独立して、水素原子、又は任意に置換されてもよいC6-14アリールを表し、ここで、置換基は、OR20及びCOOR20（R20は前記と同様である。）、酸素原子、窒素原子、炭素原子又は硫黄原子が結合してもよい糖、ハロゲン原子、並びに次式：
で示される基からなる群から選ばれる少なくとも１つであり、
各置換基は、葉酸、次式：
で示される基、アジ化物又はこれらの組み合わせを含む基でさらに置換されてもよい。
これらの中でも、本発明においては、R1、R2、R4、R5、R7、R8、R10及びR11は、水素原子を表し、
R3、R6、R9及びR12は、それぞれ独立して、任意に置換されてもよいC6-14アリールを表し、ここで、置換基は、酸素原子、窒素原子、炭素原子又は硫黄原子が結合してもよい糖、ハロゲン原子、並びに次式：
で示される基からなる群から選ばれる少なくとも１つであることが好ましい。
本発明において「これらの組み合わせを含む基」としては、例えば、次式で示される基などが挙げられる。
At least one selected from the group consisting of groups represented by:
Each substituent is folic acid, the following formula:
And a group containing an azide or a combination thereof may be further substituted.
Among these, in the present invention, R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 10 and R 11 represent a hydrogen atom,
R 3 , R 6 , R 9 and R 12 each independently represent optionally substituted C 6-14 aryl, wherein the substituent is an oxygen atom, nitrogen atom, carbon atom or sulfur A sugar to which an atom may be bonded, a halogen atom, and the following formula:
It is preferable that it is at least 1 chosen from the group which consists of group shown by these.
In the present invention, examples of the “group containing a combination thereof” include a group represented by the following formula.
また、本発明において、「アミド結合を有する基」は、-CONHCH2CH2NHCOCH2CH2COOR40（R40は前記と同様である。）で示される基であることが好ましい。
次式：
ポリエチレングリコールの場合の分子量は124(n=2)以上であり12,500(n=200)以下である。好ましくは1000〜8000であり、さらに好ましくは1000〜5000である。
In the present invention, the “group having an amide bond” is preferably a group represented by —CONHCH 2 CH 2 NHCOCH 2 CH 2 COOR 40 (R 40 is as defined above).
The following formula:
In the case of polyethylene glycol, the molecular weight is 124 (n = 2) or more and 12,500 (n = 200) or less. Preferably it is 1000-8000, More preferably, it is 1000-5000.
また本発明において、 Mは、62Znであることが好ましい。
このようなポルフィリン化合物のさらに好ましい具体例としては、例えば次式(II)、(III)、(IV)、(V)、(VI)、(VII)及び(VIII)のいずれかで示されるものを挙げることができる。
式(IV)において、R21〜R24の少なくとも一つは、硫黄原子が結合したグルコース（SGlc）であることが好ましい。
In the present invention, M is preferably 62 Zn.
More preferable specific examples of such porphyrin compounds include those represented by any of the following formulas (II), (III), (IV), (V), (VI), (VII) and (VIII): Can be mentioned.
In the formula (IV), at least one of R 21 to R 24 is preferably glucose (SGlc) to which a sulfur atom is bonded.
式(IV)において、R21がSGlc、R22、R23及びR24がフッ素原子のものを「ZnTFPP(SGlc)1」という。
R21及びR22がSGlc、R23及びR24がフッ素原子のものを「ZnTFPP(SGlc)cis-2」という。
R21及びR23がSGlc、R22及びR24がフッ素原子のものを「ZnTFPP(SGlc)trans-2」という。
R21、R22及びR23がSGlc、R24がフッ素原子のものを「ZnTFPP(SGlc)3」という。
R21、R22、R23及びR24がSGlcのものを「ZnTFPP(SGlc)4」という。
R 21 and R 22 are SGlc, those R 23 and R 24 is a fluorine atom of "ZnTFPP (SGlc) cis-2".
R 21 and R 23 are SGlc, and R 22 and R 24 are fluorine atoms are referred to as “ZnTFPP (SGlc) trans-2”.
R 21 , R 22 and R 23 are SGlc, and R 24 is a fluorine atom, which is referred to as “ZnTFPP (SGlc) 3”.
A material in which R 21 , R 22 , R 23 and R 24 are SGlc is referred to as “ZnTFPP (SGlc) 4”.
式(VI)において、R31〜R34の少なくとも一つは、エチレングリコール（EG）であることが好ましい。
式(VI)において、R31がEG、R32、R33及びR34がフッ素原子のものを「Zn1EG」という。
R31及びR32がEG、R33及びR34がフッ素原子のものを「Zncis-2EG」という。
R31及びR33がEG、R32及びR34がフッ素原子のものを「Zntrans-2EG」という。
R31、R32及びR33がEG、R34がフッ素原子のものを「Zn3EG」という。
R31、R32、R33及びR34がEGのものを「Zn4EG」という。
式(VII)で示される化合物を「Zn1propa」という。
式(VIII)で示される化合物を「ZnTFPP-triazole-TEG-FA」という。
In the formula (VI), at least one of R 31 to R 34 is preferably ethylene glycol (EG).
In the formula (VI), those in which R 31 is EG, R 32 , R 33 and R 34 are fluorine atoms are referred to as “Zn1 EG ”.
A group in which R 31 and R 32 are EG and R 33 and R 34 are fluorine atoms is referred to as “Zncis-2 EG ”.
A compound in which R 31 and R 33 are EG and R 32 and R 34 are fluorine atoms is referred to as “Zntrans-2 EG ”.
The case where R 31 , R 32 and R 33 are EG and R 34 is a fluorine atom is referred to as “Zn3 EG ”.
A case where R 31 , R 32 , R 33 and R 34 are EG is referred to as “Zn4 EG ”.
The compound represented by the formula (VII) is referred to as “Zn1 propa ”.
The compound represented by the formula (VIII) is referred to as “ZnTFPP-triazole-TEG-FA”.
さらに、本発明においては、次式(IX)：
で示される化合物（「Zn-Photofrin」）も好ましい具体例として挙げることができる。
Furthermore, in the present invention, the following formula (IX):
A compound represented by the formula (“Zn-Photofrin”) can also be mentioned as a preferred specific example.
これらの化合物は、PET診断用のトレーサーとして使用することができる。
これらの中でも、本発明のPET診断用のトレーサーとしては、次式(IV)で示される化合物が好ましく、硫黄原子が結合した糖がトランス型に配置した化合物（ZnTFPP(SGlc)trans-2）を特に好ましく使用することができる。
Among these, as the tracer for PET diagnosis of the present invention, a compound represented by the following formula (IV) is preferable, and a compound (ZnTFPP (SGlc) trans-2) in which a sugar to which a sulfur atom is bonded is arranged in a trans form is used. It can be particularly preferably used.
式(I)で示される化合物は、
次式(I')：
Formula (I '):
本発明の一態様においては、例えば、金属が導入されていないポルフィリン化合物（式(I'))含有溶液に金属イオン（例えば62Znの金属イオン）含有溶液を加えて反応させることにより、陽電子放出核種が導入されたポルフィリン化合物を得ることができる。
陽電子放出核種を導入するためのポルフィリン骨格としては、例えば、フッ素ポルフィリン(TFPP)だけでなく、テトラフェニルポルフィリン(TPP)、プロトポルフィリン、ヘマトポルフィリンなどが挙げられる。
In one embodiment of the present invention, for example, a positron emission is performed by adding a metal ion (for example, 62 Zn metal ion) -containing solution to a porphyrin compound (formula (I ′))-containing solution into which no metal is introduced, and reacting the solution. A porphyrin compound into which a nuclide has been introduced can be obtained.
Examples of the porphyrin skeleton for introducing the positron emitting nuclide include not only fluorine porphyrin (TFPP) but also tetraphenylporphyrin (TPP), protoporphyrin, hematoporphyrin, and the like.
TFPPは、式(I)で示される化合物のR3、R6、R9及びR12がC6-14アリール（例えばフェニル）で置換され、さらにC6-14アリール（例えばフェニル）がフッ素原子、糖（例えば硫黄原子が結合した糖）又はエチレングリコールで置換されたものである。
式(I')で示される化合物の製造方法は、例えば、Hirohara S. et al., Bioconjugate Chem. 2009, 20, 944-952; Hirohara S. et al., Bioorganic & Medicinal Chemistry 18 (2010) 1526-1535、F.C. Santos et al., Tetrahedron Letters, 2008, 49, 7268-7270.を参照することができる。また、式(II)、(III)及び(V)などで示されるPEG含有ポルフィリン化合物は、S. K. Sahoo et al., Bioconjugate Chem. 2002, 13, 1031-1038を参照することができる。また、市販品を用いることもできる。
TFPP is, R 3, R 6, R 9 and R 12 in compounds of formula (I) is replaced by C 6-14 aryl (e.g. phenyl), further C 6-14 aryl (e.g. phenyl) fluorine atom , Sugars (for example, sugars to which sulfur atoms are bonded) or ethylene glycol.
The method for producing the compound represented by the formula (I ′) is described, for example, in Hirohara S. et al., Bioconjugate Chem. 2009, 20, 944-952; Hirohara S. et al., Bioorganic & Medicinal Chemistry 18 (2010) 1526 -1535, FC Santos et al., Tetrahedron Letters, 2008, 49, 7268-7270. Moreover, SK Sahoo et al., Bioconjugate Chem. 2002, 13, 1031-1038 can be referred to for PEG-containing porphyrin compounds represented by the formulas (II), (III) and (V). Commercial products can also be used.
ポルフィリン化合物に陽電子放出核種を導入するには、ポルフィリン含有溶液と金属イオン含有溶液（例えば、陽電子放出核種を有する塩化亜鉛や酢酸亜鉛など）とを混合したのち、溶媒を留去すればよい。本発明においては、上記のように簡便でかつ迅速な方法でポルフィリン化合物に陽電子核種を導入することができる。
溶媒としては、ポルフィリン化合物及び金属イオンに不活性なものであればよく、例えば、ジクロロメタン、クロロホルム、トルエン、クロロベンゼン、ベンゾニトリルなどを使用できる。
In order to introduce a positron emitting nuclide into a porphyrin compound, a porphyrin-containing solution and a metal ion-containing solution (for example, zinc chloride or zinc acetate having a positron emitting nuclide) are mixed, and then the solvent is distilled off. In the present invention, a positron nuclide can be introduced into a porphyrin compound by a simple and rapid method as described above.
The solvent is not particularly limited as long as it is inert to the porphyrin compound and the metal ion. For example, dichloromethane, chloroform, toluene, chlorobenzene, benzonitrile and the like can be used.
反応は、常温で行うことができるが、必要に応じて加熱還流などを行うことが好ましい。
また、金属の導入に際しては窒素またはアルゴン雰囲気下で行うことが望ましい。
式(IX)で示される化合物も上記と同様にして得ることができる。例えば、ファイザー株式会社より市販されている「Photofrin」（登録商標）に、塩化亜鉛や酢酸亜鉛などの金属イオン含有溶液を加え、必要に応じて加熱することで得ることができる。
ポルフィリン化合物に金属イオンが導入されたことの確認は、例えば核磁気共鳴分光法（NMR）、紫外可視分光光度法(UV-Vis)や質量分析（MS）等により行なうことができる。
The reaction can be carried out at room temperature, but it is preferable to carry out heating under reflux as necessary.
In addition, it is desirable to introduce the metal in a nitrogen or argon atmosphere.
A compound represented by the formula (IX) can also be obtained in the same manner as described above. For example, it can be obtained by adding a metal ion-containing solution such as zinc chloride or zinc acetate to “Photofrin” (registered trademark) commercially available from Pfizer Inc., and heating as necessary.
Confirmation that a metal ion has been introduced into the porphyrin compound can be performed, for example, by nuclear magnetic resonance spectroscopy (NMR), ultraviolet-visible spectrophotometry (UV-Vis), mass spectrometry (MS), or the like.
以下、実施例により本発明をさらに具体的に説明する。但し、本発明はこれら実施例に限定されるものではない。 Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.
ポルフィリン化合物の合成
(1) 精製62Zn水の作製
真空中のタングステンボート中ニッケル粉を1800℃で加温溶解して蒸発させ、アルミ箔に蒸着した。このニッケル蒸着アルミ箔をターゲットとして、ニッケル蒸着面を後方に設置し、加速した3Heを入射させた。このときの最適加速エネルギーは597KeVであった。ニッケルと3He間との核反応によって、62Znが形成された。この62Znは反跳エネルギーによって後方へ放出されるので、ニッケル蒸着アルミ箔後方にKClを置き、62Znを捕捉した。この62Zn 含有KClを水溶液とし、イオン交換樹脂カラムTOYO PEARL CM-650とイオン交換水を用いて精製62Zn水を得た。
Synthesis of porphyrin compounds
(1) Preparation of purified 62 Zn water Nickel powder in a tungsten boat in a vacuum was heated and dissolved at 1800 ° C. to evaporate it and deposited on an aluminum foil. Using this nickel-deposited aluminum foil as a target, the nickel-deposited surface was placed behind, and accelerated 3 He was incident. The optimum acceleration energy at this time was 597 KeV. 62 Zn was formed by the nuclear reaction between nickel and 3 He. Since this 62 Zn was released backward by the recoil energy, KCl was placed behind the nickel-deposited aluminum foil to capture 62 Zn. The 62 Zn-containing KCl was used as an aqueous solution, and purified 62 Zn water was obtained using an ion exchange resin column TOYO PEARL CM-650 and ion exchange water.
(2) 金属が導入されていない糖鎖結合ポルフィリン化合物（1OH, cis-2OH, trans-2OH, 3OH, 4OH)の合成
市販品である5,10,15,20-テトラキス (ペンタフルオロフェニル)ポルフィリン(H2TFPP)に2,3,4,6-テトラ-O-アセチル-β-D-グルコピラノシルチオアセテート(AcGlcSAc)を反応させ、その後ナトリウムメトキシドにより糖鎖のアセチル基を脱保護した。この反応は、公知方法（Hirohara S. et al., Bioconjugate Chem. 2009, 20, 944-952; Hirohara S. et al., Bioorganic & Medicinal Chemistry 18 (2010) 1526-1535)に従って行なった。
具体的化合物の合成法を以下に示す。
(2) Synthesis of sugar chain-bound porphyrin compounds (1OH, cis-2OH, trans-2OH, 3OH, 4OH) into which no metal has been introduced 5,10,15,20-tetrakis (pentafluorophenyl) porphyrin (H 2 TFPP) was reacted with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylthioacetate (AcGlcSAc), and then the acetyl group of the sugar chain was deprotected with sodium methoxide. . This reaction was performed according to a known method (Hirohara S. et al., Bioconjugate Chem. 2009, 20, 944-952; Hirohara S. et al., Bioorganic & Medicinal Chemistry 18 (2010) 1526-1535).
A method for synthesizing specific compounds is shown below.
5-[4-(2,3,4,6-テトラ-O-アセチル-β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル)]-10,15,20-トリス(2,3,4,5,6-ペンタフルオロフェニル)ポルフィリン(1Ac)
100 mLナスフラスコにH2TFPP (49.3 mg, 50.6μmol)とAcGlcSAc(20.9mg, 51.5μmol)をDMF(10 mL)に溶解させた。この溶液にジエチルアミンを(37μL,724μmol)加えて、室温で24時間撹拌した。反応溶液をCH2Cl2で抽出した後、蒸留水(15 mL) 5回で分液した。無水硫酸ナトリウムで有機層を乾燥させた後、溶媒留去した。その後、粗生成物をシリカゲルカラムクロマトグラフィー(silicagel, CH2Cl2 to CH2Cl2/AcOEt = 100 - 60:40)で各置換体を分離した後、ゲル浸透クロマトグラフィー（GPC）により精製し１置換体(1Ac)を収率41.7%で得た。
5- [4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl)]-10,15,20- Tris (2,3,4,5,6-pentafluorophenyl) porphyrin (1Ac)
H 2 TFPP (49.3 mg, 50.6 μmol) and AcGlcSAc (20.9 mg, 51.5 μmol) were dissolved in DMF (10 mL) in a 100 mL eggplant flask. Diethylamine (37 μL, 724 μmol) was added to this solution and stirred at room temperature for 24 hours. The reaction solution was extracted with CH 2 Cl 2 and then separated with distilled water (15 mL) 5 times. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The crude product is then separated by silica gel column chromatography (silicagel, CH 2 Cl 2 to CH 2 Cl 2 / AcOEt = 100-60:40) and then purified by gel permeation chromatography (GPC). The monosubstituted product (1Ac) was obtained with a yield of 41.7%.
5,10-ビス[4-(2,3,4,6-テトラ-O-アセチル-β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル)]-15,20-ビス (2,3,4,5,6-ペンタフルオロフェニル)ポルフィリン (cis-2Ac)
H2TFPP (50.0 mg, 51.3μmol), AcGlcSAc(41.6 mg,102.5μmol)を用いて１置換体の合成法と同様の合成法により、cis-2置換体(cis-2Ac)を収率18.5%で得た。
5,10-bis [4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl)]-15,20 -Bis (2,3,4,5,6-pentafluorophenyl) porphyrin (cis-2Ac)
The cis-2 substituent (cis-2Ac) was obtained in a yield of 18.5% by the same synthesis method as the monosubstitution method using H 2 TFPP (50.0 mg, 51.3 μmol) and AcGlcSAc (41.6 mg, 102.5 μmol). I got it.
5,15-ビス[4-(2,3,4,6-テトラ-O-アセチル-β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル)]-10,20-ビス(2,3,4,5,6-ペンタフルオロフェニル)ポルフィリン (trans-2Ac)
H2TFPP (50.0 mg, 51.3μmol), AcGlcSAc(41.6 mg,102.5μmol)を用いて１置換体の合成法と同様の合成法により、trans-2置換体(trans-2Ac)を収率13.5%で得た。
5,15-bis [4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl)]-10,20 -Bis (2,3,4,5,6-pentafluorophenyl) porphyrin (trans-2Ac)
The trans-2 substituent (trans-2Ac) was obtained in a yield of 13.5% by the same synthesis method as the monosubstitution method using H 2 TFPP (50.0 mg, 51.3 μmol) and AcGlcSAc (41.6 mg, 102.5 μmol). I got it.
5,10,15-トリス[4-(2,3,4,6-テトラ-O-アセチル-β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル)]-20-(2,3,4,5,6-ペンタフルオロフェニル) ポルフィリン (3Ac)
H2TFPP (49.5 mg, 50.8μmol), AcGlcSAc(61.9 mg,152.5μmol)を用いて１置換体の合成法と同様の合成法により、3置換体(3Ac)を収率31.5%で得た。
5,10,15-Tris [4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl)]-20 -(2,3,4,5,6-pentafluorophenyl) porphyrin (3Ac)
The 3-substituted product (3Ac) was obtained in a yield of 31.5% by a synthesis method similar to the synthesis method of 1-substituted product using H 2 TFPP (49.5 mg, 50.8 μmol) and AcGlcSAc (61.9 mg, 152.5 μmol).
5,10,15,20-テトラキス(4-(2,3,4,6-テトラ-O-アセチル-β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル) ポルフィリン (4Ac)
H2TFPP (64.9 mg, 66.6μmol), AcGlcSAc(113 mg, 278μmol)を用いて１置換体の同様の合成法により、4置換体(4Ac)を収率74.0%で得た。
5,10,15,20-tetrakis (4- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl) porphyrin (4Ac)
A 4-substituent (4Ac) was obtained in a yield of 74.0% by the same synthesis method of the 1-substituent using H 2 TFPP (64.9 mg, 66.6 μmol) and AcGlcSAc (113 mg, 278 μmol).
5-[4-(β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル)]-10,15,20-トリス (2,3,4,5,6-ペンタフルオロフェニル) ポルフィリン (1OH)
100 mLナスフラスコに、1Ac(23.7 mg, 18.0μmol)をCH2Cl2(20 mL)とMeOH(20 mL)の混合溶液に溶解させた。この溶液にpH9になるようにナトリウムメトキシドを加えた。この溶液を、45〜50℃の水浴で約10分間還流した。反応溶液に酢酸を加え中和した後、溶媒留去した。粗生成物を逆相カラムクロマトグラフィー(acetonitrile / H2O = 8 / 2)により精製し、1OHを60.9%で得た。
5- [4- (β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl)]-10,15,20-tris (2,3,4,5,6-pentafluoro Phenyl) porphyrin (1OH)
In a 100 mL eggplant flask, 1Ac (23.7 mg, 18.0 μmol) was dissolved in a mixed solution of CH 2 Cl 2 (20 mL) and MeOH (20 mL). Sodium methoxide was added to this solution to pH 9. The solution was refluxed for about 10 minutes in a 45-50 ° C. water bath. Acetic acid was added to the reaction solution for neutralization, and then the solvent was distilled off. The crude product was purified by reverse phase column chromatography (acetonitrile / H 2 O = 8/2) to obtain 1OH at 60.9%.
5,10-ビス[4-(β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル)]-15,20-ビス (2,3,4,5,6-ペンタフルオロフェニル) ポルフィリン (cis-2OH)
cis-2Ac (81.2 mg, 48.8μmol)を用いて１置換体(1OH)の同様の合成法により、cis-2置換体(cis-2OH)を収率54.9%で得た。
5,10-bis [4- (β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl)]-15,20-bis (2,3,4,5,6-penta Fluorophenyl) porphyrin (cis-2OH)
A cis-2 substituted product (cis-2OH) was obtained in a yield of 54.9% by the same synthesis method of the 1 substituted product (1OH) using cis-2Ac (81.2 mg, 48.8 μmol).
5,15-ビス[4-(β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル)]-10,20-ビス (2,3,4,5,6-ペンタフルオロフェニル) ポルフィリン(trans-2OH)
trans-2Ac (23.2 mg, 13.9μmol)を用いて１置換体(1OH)の同様の合成法により、trans-2置換体(trans-2OH)を収率50.9%で得た。
5,15-bis [4- (β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl)]-10,20-bis (2,3,4,5,6-penta Fluorophenyl) porphyrin (trans-2OH)
A trans-2 substituent (trans-2OH) was obtained in a yield of 50.9% by the same synthesis method of the monosubstitution (1OH) using trans-2Ac (23.2 mg, 13.9 μmol).
5,10,15-トリス[4-(β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル)]-20-ビス (2,3,4,5,6-ペンタフルオロフェニル) ポルフィリン (3OH)
3Ac (47.9 mg, 23.9μmol)を用いて１置換体(1OH)の同様の合成法により、3置換体(3OH)を収率52.4%で得た。
5,10,15-Tris [4- (β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl)]-20-bis (2,3,4,5,6-penta Fluorophenyl) porphyrin (3OH)
By using the same synthesis method of mono-substituted product (1OH) using 3Ac (47.9 mg, 23.9 μmol), 3-substituted product (3OH) was obtained in a yield of 52.4%.
5,10,15,20-テトラキス(4-(β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル) ポルフィリン (4OH)
4Ac (51.1 mg, 21.7μmol)を用いて１置換体(1OH)の同様の合成法により、4置換体(4OH)を収率68.8%で得た。
5,10,15,20-tetrakis (4- (β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl) porphyrin (4OH)
By using the same synthesis method of mono-substituted product (1OH) using 4Ac (51.1 mg, 21.7 μmol), 4-substituted product (4OH) was obtained in a yield of 68.8%.
(3) 金属が導入された糖鎖結合ポルフィリン化合物の合成
上記のとおり作製したサンプルにZn核を下記のように導入した。なお、65Zn含有ポルフィリン誘導体及び62Zn含有ポルフィリン誘導体は、(3-3)のように金属が導入されていない各フリーベースポルフィリン誘導体に65Zn核または62Zn核を導入することにより合成した。
(3) Synthesis of sugar chain-bound porphyrin compound into which metal was introduced Zn nuclei were introduced into the sample prepared as described above as follows. The 65 Zn-containing porphyrin derivative and the 62 Zn-containing porphyrin derivative were synthesized by introducing a 65 Zn nucleus or a 62 Zn nucleus into each free base porphyrin derivative in which no metal was introduced as in (3-3).
(3-1) 65Zn含有ポルフィリン誘導体の合成
150μM in MeOHのポルフィリン溶液を30 mLナスフラスコに264μL分注し、65ZnCl2in MeOHを26.4μL (26.5 kBq)を加えた。その後、ナスフラスコをエバポレータで回転させながら10分間ドライヤーで加熱した後、溶媒留去した。その後、ナスフラスコに生化学用DMSOを396μL加えたのち、2 mLのエッペンチューブに溶液を移した。その後10分間溶液を静置させ殺菌した。
(3-1) Synthesis of 65 Zn-containing porphyrin derivatives
264 μL of 150 μM in MeOH porphyrin solution was dispensed into a 30 mL eggplant flask, and 26.4 μL (26.5 kBq) of 65 ZnCl 2 in MeOH was added. Thereafter, the eggplant flask was heated with a dryer for 10 minutes while rotating with an evaporator, and then the solvent was distilled off. Thereafter, 396 μL of biochemical DMSO was added to the eggplant flask, and then the solution was transferred to a 2 mL Eppendorf tube. Thereafter, the solution was allowed to stand for 10 minutes to sterilize.
(3-2) 62Zn含有ポルフィリン誘導体の合成
150μM in MeOHのポルフィリン溶液を10 mLナスフラスコに317μL分注し、62ZnCl2in MeOHを31.7μL (31.7 kBq)を加えた。その後、ナスフラスコをエバポレータで回転させながら10分間ドライヤーで加熱した後、溶媒留去した。その後、ナスフラスコに生化学用DMSOを317μL加えたのち、2 mLのエッペンチューブに溶液を移した。その後10分間溶液を静置させ殺菌した。
(3-2) Synthesis of 62 Zn-containing porphyrin derivatives
317 μL of a 150 μM in MeOH porphyrin solution was dispensed into a 10 mL eggplant flask, and 31.7 μL (31.7 kBq) of 62 ZnCl 2 in MeOH was added. Thereafter, the eggplant flask was heated with a dryer for 10 minutes while rotating with an evaporator, and then the solvent was distilled off. Then, after adding 317 μL of biochemical DMSO to the eggplant flask, the solution was transferred to a 2 mL Eppendorf tube. Thereafter, the solution was allowed to stand for 10 minutes to sterilize.
(3-3)64Zn含有ポルフィリン誘導体の合成
5-[4-(β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル]-10,15,20-トリス (ペンタフルオロフェニル)ポルフィナート亜鉛(II) (Zn1OHまたは64ZnTFPP(SGlc)1)
50 mLナスフラスコに1OH (53.0 mg, 46.1μmol)とメタノール10 mLを加え、化合物を溶解させた。このナスフラスコに安定同位体元素である64Zn核を有する塩化亜鉛(31.3 mg, 231μmol)を加え10分間加熱還流させた。その後、粗生成物をゲル浸透クロマトグラフィー(LH20)で精製し、目的化合物Zn1OHを収率89.3%で得た。
Purity(HPLC): 99%. Anal. Calcd. for C50H19O5N4F19SZn + CH3CN: C, 47.84; H, 1.53; N, 4.46. Found: C, 47.97; H, 1.76; N, 4.84. 1H NMR (600.17 MHz, CD3OD, CHD2OD = 3.30 ppm):δ(ppm) = 9.03 (8H, brs, 2,3,7,8,12,13,17,18-pyrroleH), 5.10 (1H, d, 3J = 8.5 Hz, 1-GlcH), 3.93 (1H, m, 6-GlcH), 3.71 (1H, m, 6-GlcH), 3.49-3.38 (4H, m, 2,3,4,5-GlcH). 13C NMR (150.92 MHz, CD3OD, CD3OD = 49.0 ppm):δ(ppm) = 151.7 (1,9,11,14,16,19-pyrroleC), 151.6 (4,6-pyrroleC), 149.3, 147.6 (5-(2,6-PhC)), 148.9, 147.2 (10,15,20-(2,6-PhC)), 148.5, 146.9 (5-(3,5-PhC)), 144.3, 142.6 (10,15,20-(4-PhC)), 139.9, 138.2 (10,15,20-(3,5-PhC)), 133.2 (3,7-pyrroleC), 133.0 (2,8,12,13,17,18-pyrroleC), 123.5 (5-(4-PhC)), 118.4 (1-PhC), 113.3 (5-(1-PhC)), 106.0 (5-mesoC), 104.8 (10,15,20-mesoC), 87.0 (1-GlcC), 82.7 (5-GlcC), 79.8 (3-GlcC), 76.0 (2-GlcC), 71.7 (4-GlcC), 63.1 (6-GlcC). 19F NMR (564.72 MHz, CD3OD, CF3CO2H = -76.50 ppm):δ(ppm) = -133.6 (2F, m, 5-(3,5-PhF)), -137.9 (6F, m, 10,15,20-(3,5-PhF)), -138.2 (2F, m, 5-(2,6-PhF)), -154.4 (3F, m, 10,15,20-(4-PhF)), -163.6 (6F, m, 10,15,20-(2,6-PhF)). UV-vis (c = 1.00μM, DMSO, path length = 1 cm, 25°C):λ/ nm(ε×10-4 / M-1cm-1) = 423 (50.8), 553 (2.65), 587 (0.38).
(3-3) Synthesis of 64 Zn-containing porphyrin derivatives
5- [4- (β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl] -10,15,20-tris (pentafluorophenyl) porphinate zinc (II) (Zn1OH or 64 ZnTFPP (SGlc) 1)
1OH (53.0 mg, 46.1 μmol) and 10 mL of methanol were added to a 50 mL eggplant flask to dissolve the compound. To this eggplant flask, zinc chloride (31.3 mg, 231 μmol) having 64 Zn nuclei as a stable isotope element was added and heated to reflux for 10 minutes. Thereafter, the crude product was purified by gel permeation chromatography (LH20) to obtain the target compound Zn1OH in a yield of 89.3%.
Purity (HPLC): 99%. Anal. Calcd. For C 50 H 19 O 5 N 4 F 19 SZn + CH 3 CN: C, 47.84; H, 1.53; N, 4.46. Found: C, 47.97; H, 1.76 ; N, 4.84. 1 H NMR (600.17 MHz, CD 3 OD, CHD 2 OD = 3.30 ppm): δ (ppm) = 9.03 (8H, brs, 2,3,7,8,12,13,17,18 -pyrroleH), 5.10 (1H, d, 3 J = 8.5 Hz, 1-GlcH), 3.93 (1H, m, 6-GlcH), 3.71 (1H, m, 6-GlcH), 3.49-3.38 (4H, m , 2,3,4,5-GlcH) .13C NMR (150.92 MHz, CD 3 OD, CD 3 OD = 49.0 ppm): δ (ppm) = 151.7 (1,9,11,14,16,19-pyrroleC ), 151.6 (4,6-pyrroleC), 149.3, 147.6 (5- (2,6-PhC)), 148.9, 147.2 (10,15,20- (2,6-PhC)), 148.5, 146.9 (5 -(3,5-PhC)), 144.3, 142.6 (10,15,20- (4-PhC)), 139.9, 138.2 (10,15,20- (3,5-PhC)), 133.2 (3, 7-pyrroleC), 133.0 (2,8,12,13,17,18-pyrroleC), 123.5 (5- (4-PhC)), 118.4 (1-PhC), 113.3 (5- (1-PhC)) , 106.0 (5-mesoC), 104.8 (10,15,20-mesoC), 87.0 (1-GlcC), 82.7 (5-GlcC), 79.8 (3-GlcC), 76.0 (2-GlcC), 71.7 (4 -GlcC), 63.1 (6-GlcC) .19F NMR (564.72 MHz, CD 3 OD, CF 3 CO 2 H = -76.50 ppm): δ (ppm) = -133.6 (2F, m, 5- (3,5 -PhF)), -137.9 (6F, m, 10,15,20- (3,5-PhF) ), -138.2 (2F, m, 5- (2,6-PhF)), -154.4 (3F, m, 10,15,20- (4-PhF)), -163.6 (6F, m, 10,15 , 20- (2,6-PhF)). UV-vis (c = 1.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 -4 / M -1 cm -1 ) = 423 (50.8), 553 (2.65), 587 (0.38).
5,10-ビス[4-(β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル]-15,20-ビス (ペンタフルオロフェニル)ポルフィナート亜鉛(II) (Zncis-2OHまたは64ZnTFPP(SGlc)cis-2)
cis-2OH (37.5 mg, 28.3μmol)を用いて1OHと同様の実験を行い、目的化合物Zncis-2OHを86.6%で得た。
Purity(HPLC): 99%. Anal. Calcd. for C56H30O10N4F18S2Zn + 2CH3CN: C, 45.68; H, 2.05; N, 3.80. Found: C, 46.12; H, 2.23; N, 4.94. 1H NMR (600.17 MHz, CD3OD, CHD2OD = 3.30 ppm):δ(ppm) = 9.03 (8H, m, 2,3,7,8,12,13,17,18-pyrroleH), 5.17 (2H, d, 3J = 8.0 Hz, 1-GlcH), 3.94 (2H, m, 6-GlcH), 3.70 (2H, m, 6-GlcH), 3.50-3.39 (8H, m, 2,3,4,5-GlcH). 13C NMR (150.92 MHz, CD3OD, CD3OD = 49.0 ppm):δ(ppm) = 151.7 (1,14,16,19-pyrroleC), 151.6 (4,6,9,11-pyrroleC), 149.4, 147.7 (5,10-(2,6-PhC)), 148.9, 147.3 (15,20-(2,6-PhC)), 148.6, 147.0 (5,10-(3,5-PhC)), 144.3, 142.6 (15,20-(4-PhC)), 139.8, 138.2 (15,20-(3,5-PhC)), 133.2 (3,7,8,12-pyrroleC), 132.9 (2,13,17,18-pyrroleC), 123.6 (5,10-(4-PhC)), 118.4 (15,20-(1-PhC)), 114.2 (5,10-(1-PhC)), 105.9 (5,10-mesoC), 104.7 (15,20-mesoC), 86.9 (1-GlcC), 82.7 (5-GlcC), 79.8 (3-GlcC), 76.0 (2-GlcC), 71.7 (4-GlcC), 63.1 (6-GlcC). 19F NMR (564.72 MHz, CD3OD, CF3CO2H = -76.50 ppm):δ(ppm) = -133.3 (4F, m, 5,10-(3,5-PhF)), -137.6 (4F, 15,20-(3,5-PhF)), -137.9 (4F, m, 5,10-(2,6-PhF)), -154.2 (2F, m, 15,20-(4-PhF)), -163.3 (4F, m, 15,20-(2,6-PhF)). UV-vis (c = 1.00μM, DMSO, path length = 1 cm, 25°C):λ/ nm(ε×10-4 / M-1cm-1) = 424 (52.0), 553 (2.73), 587 (0.35).
5,10-bis [4- (β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl] -15,20-bis (pentafluorophenyl) porphinate zinc (II) (Zncis -2OH or 64 ZnTFPP (SGlc) cis-2)
The same experiment as 1OH was performed using cis-2OH (37.5 mg, 28.3 μmol), and the target compound Zncis-2OH was obtained at 86.6%.
Purity (HPLC): 99%. Anal. Calcd. For C 56 H 30 O 10 N 4 F 18 S 2 Zn + 2CH 3 CN: C, 45.68; H, 2.05; N, 3.80. Found: C, 46.12; H , 2.23; N, 4.94. 1 H NMR (600.17 MHz, CD 3 OD, CHD 2 OD = 3.30 ppm): δ (ppm) = 9.03 (8H, m, 2,3,7,8,12,13,17 , 18-pyrroleH), 5.17 (2H, d, 3 J = 8.0 Hz, 1-GlcH), 3.94 (2H, m, 6-GlcH), 3.70 (2H, m, 6-GlcH), 3.50-3.39 (8H , m, 2,3,4,5-GlcH) 13 C NMR (150.92 MHz, CD 3 OD, CD 3 OD = 49.0 ppm):. δ (ppm) = 151.7 (1,14,16,19-pyrroleC) , 151.6 (4,6,9,11-pyrroleC), 149.4, 147.7 (5,10- (2,6-PhC)), 148.9, 147.3 (15,20- (2,6-PhC)), 148.6, 147.0 (5,10- (3,5-PhC)), 144.3, 142.6 (15,20- (4-PhC)), 139.8, 138.2 (15,20- (3,5-PhC)), 133.2 (3 , 7,8,12-pyrroleC), 132.9 (2,13,17,18-pyrroleC), 123.6 (5,10- (4-PhC)), 118.4 (15,20- (1-PhC)), 114.2 (5,10- (1-PhC)), 105.9 (5,10-mesoC), 104.7 (15,20-mesoC), 86.9 (1-GlcC), 82.7 (5-GlcC), 79.8 (3-GlcC) , 76.0 (2-GlcC), 71.7 (4-GlcC), 63.1 (6-GlcC) 19 F NMR (564.72 MHz, CD 3 OD, CF 3 CO 2 H = -76.50 ppm): δ (ppm) = -. 133.3 (4F, m, 5,10- (3,5-PhF)), -137.6 (4F, 15 , 20- (3,5-PhF)), -137.9 (4F, m, 5,10- (2,6-PhF)), -154.2 (2F, m, 15,20- (4-PhF)), . -163.3 (4F, m, 15,20- (2,6-PhF)) UV-vis (c = 1.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 - 4 / M -1 cm -1 ) = 424 (52.0), 553 (2.73), 587 (0.35).
5,15-ビス[4-(β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル]-10,20-ビス (ペンタフルオロフェニル) ポルフィナート亜鉛(II) (Zntrans-2OHまたは64ZnTFPP(SGlc)trans-2)
trans-2OH (30.1 mg, 22.7μmol)を用いて1OHと同様の実験を行い、目的化合物Zntrans-2OHを91.7%で得た。
Purity(HPLC): 99%. Anal. Calcd. for C56H30O10N4F18S2Zn + 2CH3CN: C, 45.68 H, 2.05; N, 3.80. Found: C, 45.89; H, 2.38; N, 5.44. 1H NMR (600.17 MHz, CD3OD, CHD2OD = 3.30 ppm):δ(ppm) = 9.01 (8H, brs, 2,3,7,8,12,13,17,18-pyrroleH), 5.11 (2H, d, 3J = 7.6 Hz, 1-GlcH), 3.94 (2H, m, 6-GlcH), 3.71 (2H, m, 6-GlcH), 3.49-3.38 (8H, m, 2,3,4,5-GlcH). 13C NMR (150.92 MHz, CD3OD, CD3OD = 49.0 ppm):δ(ppm) = 151.7 (1,9,11,19-pyrroleC), 151.6 (4,6,14,16-pyrroleC), 149.3, 147.6 (5,15-(2,6-PhC)), 148.9, 147.3 (10,20-(2,6-PhC)), 148.6, 146.9 (5,15-(3,5-PhC)), 144.2, 142.6 (10,20-(4-PhC)), 139.9, 138.2 (10,20-(3,5-PhC)), 133.2 (3,7,13,17-pyrroleC), 132.9 (2,8,12,18-pyrroleC), 123.6 (5,15-(4-PhC)), 118.4 (10,20-(1-PhC)), 114.2 (5,15-(1-PhC)), 105.9 (5,15-mesoC), 104.7 (10,20-mesoC), 87.0 (1-GlcC), 82.7 (5-GlcC), 79.8 (3-GlcC), 76.0 (2-GlcC), 71.7 (4-GlcC), 63.0 (6-GlcC). 19F NMR (564.72 MHz, CD3OD, CF3CO2H = -76.55 ppm):δ(ppm) = -133.5 (4F, m, 5,15-(3,5-PhF)), -137.7 (4F, m, 10,20-(3,5-PhF)), -138.1 (4F, m, 5,15-(2,6-PhF)), -154.4 (2F, m, 10,20-(4-PhF)), -163.3 (4F, m, 10,20-(2,6-PhF)). UV-vis (c = 1.00μM, DMSO, path length = 1 cm, 25°C):λ/ nm(ε×10-4 / M-1cm-1) = 424 (52.5), 553 (2.82), 588 (0.37).
5,15-bis [4- (β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl] -10,20-bis (pentafluorophenyl) porphinate zinc (II) (Zntrans -2OH or 64 ZnTFPP (SGlc) trans-2)
An experiment similar to 1OH was performed using trans-2OH (30.1 mg, 22.7 μmol), and the target compound Zntrans-2OH was obtained at 91.7%.
Purity (HPLC): 99%. Anal. Calcd. For C 56 H 30 O 10 N 4 F 18 S 2 Zn + 2CH 3 CN: C, 45.68 H, 2.05; N, 3.80. Found: C, 45.89; H, 2.38; N, 5.44. 1 H NMR (600.17 MHz, CD 3 OD, CHD 2 OD = 3.30 ppm): δ (ppm) = 9.01 (8H, brs, 2,3,7,8,12,13,17, 18-pyrroleH), 5.11 (2H, d, 3 J = 7.6 Hz, 1-GlcH), 3.94 (2H, m, 6-GlcH), 3.71 (2H, m, 6-GlcH), 3.49-3.38 (8H, . m, 2,3,4,5-GlcH) 13 C NMR (150.92 MHz, CD 3 OD, CD 3 OD = 49.0 ppm): δ (ppm) = 151.7 (1,9,11,19-pyrroleC), 151.6 (4,6,14,16-pyrroleC), 149.3, 147.6 (5,15- (2,6-PhC)), 148.9, 147.3 (10,20- (2,6-PhC)), 148.6, 146.9 (5,15- (3,5-PhC)), 144.2, 142.6 (10,20- (4-PhC)), 139.9, 138.2 (10,20- (3,5-PhC)), 133.2 (3, 7,13,17-pyrroleC), 132.9 (2,8,12,18-pyrroleC), 123.6 (5,15- (4-PhC)), 118.4 (10,20- (1-PhC)), 114.2 ( 5,15- (1-PhC)), 105.9 (5,15-mesoC), 104.7 (10,20-mesoC), 87.0 (1-GlcC), 82.7 (5-GlcC), 79.8 (3-GlcC), . 76.0 (2-GlcC), 71.7 (4-GlcC), 63.0 (6-GlcC) 19 F NMR (564.72 MHz, CD 3 OD, CF 3 CO 2 H = -76.55 ppm): δ (ppm) = -133.5 (4F, m, 5,15- (3,5-PhF)), -137.7 (4F, m , 10,20- (3,5-PhF)), -138.1 (4F, m, 5,15- (2,6-PhF)), -154.4 (2F, m, 10,20- (4-PhF) ), -163.3 (4F, m, 10,20- (2,6-PhF)). UV-vis (c = 1.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 -4 / M -1 cm -1 ) = 424 (52.5), 553 (2.82), 588 (0.37).
5,10,15-トリス [4-(β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル]-20-ペンタフルオロフェニル)ポルフィナート亜鉛(II) (Zn3OHまたは64ZnTFPP(SGlc)3)
3OH (64.0 mg, 42.6μmol)を用いてZn1OHと同様の実験を行い、目的化合物Zn3OHを87.4%で得た。
Purity(HPLC): 98%. Anal. Calcd. for C62H41O15N4F17S3+ H2O + 2CH3CN: C, 44.68; H, 2.60; N, 3.36. Found: C, 44.6; H, 2.84; N, 4.40. 1H NMR (600.17 MHz, CD3OD, CHD2OD = 3.30 ppm):δ(ppm) = 9.00 (8H, m, 2,3,7,8,12,13,17,18-pyrroleH), 5.10 (3H, d, 3J = 8.2 Hz, 1-GlcH), 3.94 (3H, m, 6-GlcH), 3.71 (3H, m, 6-GlcH), 3.49-3.38 (12H, m, 2,3,4,5-GlcH). 13C NMR (150.92 MHz, CD3OD, CD3OD = 49.0 ppm):δ(ppm) = 151.7 (1,19-pyrroleC), 151.6 (4,6,9,11,14,16-pyrroleC), 149.3, 147.6 (5,10,15-(2,6-PhC)), 148.9, 147.2 (20-(2,6-PhC)), 148.5, 146.9 (5,10,15-(3,5-PhC)), 144.3, 142.6 (20-(4-PhC)), 139.8, 138.2 (20-(3,5-PhC)), 133.1 (3,7,8,12,13,17-pyrroleC), 132.9 (2,18-pyrroleC), 123.6 (5,10,15-(4-PhC)), 118.4 (20-(1-PhC)), 114.2 (5,10,15-(1-PhC)), 105.8 (5,10,15-mesoC), 104.6 (20-mesoC), 86.9 (1-GlcC), 82.7 (5-GlcC), 79.8 (3-GlcC), 76.0 (2-GlcC), 71.7 (4-GlcC), 63.1 (6-GlcC). 19F NMR (564.72 MHz, CD3OD, CF3CO2H = -76.50 ppm):δ(ppm) = -133.3 (6F, m, 5,10,15-(3,5-PhF)), -137.6 (2F, m, 20-(3,5-PhF)), -137.9 (6F, m, 5,10,15-(2,6-PhF)), -154.2 (1F, m, 20-(4-PhF)), -163.3 (2F, m, 20-(2,6-PhF)). UV-vis (c = 1.00μM, DMSO, path length = 1 cm, 25°C):λ/ nm (ε×10-4 / M-1cm-1) = 424 (51.6), 553 (2.69), 588 (0.35).
5,10,15-Tris [4- (β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl] -20-pentafluorophenyl) porphinate zinc (II) (Zn3OH or 64 ZnTFPP (SGlc) 3)
The same experiment as Zn1OH was performed using 3OH (64.0 mg, 42.6 μmol), and the target compound Zn3OH was obtained at 87.4%.
Purity (HPLC): 98%. Anal. Calcd. For C 62 H 41 O 15 N 4 F 17 S 3 + H 2 O + 2CH 3 CN: C, 44.68; H, 2.60; N, 3.36. Found: C, 44.6; H, 2.84; N, 4.40. 1 H NMR (600.17 MHz, CD 3 OD, CHD 2 OD = 3.30 ppm): δ (ppm) = 9.00 (8H, m, 2,3,7,8,12, 13,17,18-pyrroleH), 5.10 (3H, d, 3 J = 8.2 Hz, 1-GlcH), 3.94 (3H, m, 6-GlcH), 3.71 (3H, m, 6-GlcH), 3.49- . 3.38 (12H, m, 2,3,4,5 -GlcH) 13 C NMR (150.92 MHz, CD 3 OD, CD 3 OD = 49.0 ppm): δ (ppm) = 151.7 (1,19-pyrroleC), 151.6 (4,6,9,11,14,16-pyrroleC), 149.3, 147.6 (5,10,15- (2,6-PhC)), 148.9, 147.2 (20- (2,6-PhC)) , 148.5, 146.9 (5,10,15- (3,5-PhC)), 144.3, 142.6 (20- (4-PhC)), 139.8, 138.2 (20- (3,5-PhC)), 133.1 ( 3,7,8,12,13,17-pyrroleC), 132.9 (2,18-pyrroleC), 123.6 (5,10,15- (4-PhC)), 118.4 (20- (1-PhC)), 114.2 (5,10,15- (1-PhC)), 105.8 (5,10,15-mesoC), 104.6 (20-mesoC), 86.9 (1-GlcC), 82.7 (5-GlcC), 79.8 (3 . -GlcC), 76.0 (2- GlcC), 71.7 (4-GlcC), 63.1 (6-GlcC) 19 F NMR (564.72 MHz, CD 3 OD, CF 3 CO 2 H = -76.50 ppm): δ (ppm ) = -133.3 (6F, m, 5,10,15- (3,5-PhF)), -137.6 (2F, m, 20- (3,5-PhF)), -137.9 (6F, m, 5,10,15- (2,6-PhF)), -154.2 (1F, m, 20- (4- PhF)), -163.3 (2F, m, 20- (2,6-PhF)). UV-vis (c = 1.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 -4 / M -1 cm -1 ) = 424 (51.6), 553 (2.69), 588 (0.35).
5,10,15,20-テトラキス(4-(β-D-グルコピラノシルチオ)-2,3,5,6-テトラフルオロフェニル) ペンタフルオロフェニル) ポルフィナート亜鉛(II) (Zn4OHまたは64ZnTFPP(SGlc)4)
4OH (50.5 mg, 30.1μmol)を用いてZn1OHと同様の実験を行い、目的化合物Zn4OHを79.9%で得た。
Anal. calcd. for C68H52O20N4F16S4Zn + 10H2O: C, 42.47; H, 2.73; N, 2.91. Found: C, 42.50; H, 3.34; N, 2.85. 1H NMR (600.07 MHz, CD3OD, CHD2OD = 3.30 ppm):δ(ppm) = 8.99 (8H, s,β-pyrroleH), 5.08 (4H, m, 1-GlcH), 3.91 (4H, m, 6-GlcH), 3.69 (4H, m, 6-GlcH), 3.44 - 3.22 (16H, m, 2,3,4,5-GlcH). 13C NMR (100.40 MHz, CD3OD, CD3OD = 49.0 ppm):δ(ppm) = 151.20 (α-pyrroleC), 149.11 (2,6-PhC), 146.67 (3,5-PhC), 133.77 - 131.87 (β-pyrroleC), 132.82 (4-PhC), 123.47 (1-PhC), 114.00 (mesoC), 86.69 (1-GlcC), 82.80 (5-GlcC), 79.25 (3-GlcC), 75.43 (2-GlcC), 71.07 (4-GlcC), 63.13 (6-GlcC). 19F NMR (376 MHz, CD3OD, CF3CO2H = -76.05 ppm):δ(ppm) = -134.06 (8F, dd, 3JF-F = 24 Hz, 5JF-F= 12 Hz, 3,5-PhF), -138.57 (8F, dd, 3JF-F = 26 Hz, 5JF-F= 12 Hz, 2,6-PhF). UV-vis (c = 5.16μM, DMSO, path length = 1 cm, 25 oC):λ/ nm (ε×10-3 / M-1・cm-1) = 425 (50.2), 554 (2.63), 597 (0.16). FL (c = 5.16μM, DMSO, path length = 1 cm,λex = 415 nm, 25 oC):λ/ nm = 599, 650.
5,10,15,20-tetrakis (4- (β-D-glucopyranosylthio) -2,3,5,6-tetrafluorophenyl) pentafluorophenyl) porphinate zinc (II) (Zn4OH or 64 ZnTFPP (SGlc) 4)
The same experiment as Zn1OH was performed using 4OH (50.5 mg, 30.1 μmol), and the target compound Zn4OH was obtained at 79.9%.
Anal.calcd.for C 68 H 52 O 20 N 4 F 16 S 4 Zn + 10H 2 O: C, 42.47; H, 2.73; N, 2.91. Found: C, 42.50; H, 3.34; N, 2.85. 1 H NMR (600.07 MHz, CD 3 OD, CHD 2 OD = 3.30 ppm): δ (ppm) = 8.99 (8H, s, β-pyrroleH), 5.08 (4H, m, 1-GlcH), 3.91 (4H, m , 6-GlcH), 3.69 (4H, m, 6-GlcH), 3.44-3.22 (16H, m, 2,3,4,5-GlcH). 13 C NMR (100.40 MHz, CD 3 OD, CD 3 OD = 49.0 ppm): δ (ppm) = 151.20 (α-pyrroleC), 149.11 (2,6-PhC), 146.67 (3,5-PhC), 133.77-131.87 (β-pyrroleC), 132.82 (4-PhC) , 123.47 (1-PhC), 114.00 (mesoC), 86.69 (1-GlcC), 82.80 (5-GlcC), 79.25 (3-GlcC), 75.43 (2-GlcC), 71.07 (4-GlcC), 63.13 ( 19 F NMR (376 MHz, CD 3 OD, CF 3 CO 2 H = -76.05 ppm): δ (ppm) = -134.06 (8F, dd, 3 J FF = 24 Hz, 5 J FF = 12 Hz, 3,5-PhF), -138.57 (8F, dd, 3 J FF = 26 Hz, 5 J FF = 12 Hz, 2,6-PhF). UV-vis (c = 5.16μM, DMSO, path length = 1 cm, 25 oC) :. λ / nm (ε × 10 -3 / M -1 · cm -1) = 425 (50.2), 554 (2.63), 597 (0.16) FL (c = 5.16μM, DMSO, path length = 1 cm, λ ex = 415 nm, 25 oC): λ / nm = 599, 650.
(3-4) エチレングリコール結合ポルフィリン化合物(62Zn-TFPP-(EG)3またはZn3EG)の合成
テトラフルオロ-プロトポルフィリン（エチレングリコール(EG))3メタノール溶液と62Zn水を3：1で混和し、70℃10分処理することで62Zn-TFPP-(EG)3を得た。反応後、溶液のメタノールを加温で分溜し、ゲルクロマトグラフィー（LH20）で精製することで目的の62Zn-TFPP-(EG)3水溶液とした。405nmの吸収を測定し、標品の値と比較して濃度決定した。
(3-4) ethylene glycol binding porphyrin compound (62 Zn-TFPP- (EG) 3 or Zn3EG) Synthesis tetrafluoro of - protoporphyrin (ethylene glycol (EG)) 3 methanol solution and 62 Zn water 3: mixed with 1 Then, 62 Zn-TFPP- (EG) 3 was obtained by treatment at 70 ° C. for 10 minutes. After the reaction, methanol in the solution was distilled by heating and purified by gel chromatography (LH20) to obtain the desired 62 Zn-TFPP- (EG) 3 aqueous solution. Absorbance at 405 nm was measured and the concentration was determined by comparison with the standard value.
本実施例は、合成されたポルフィリン誘導体（ZnTFPP(SGlc)trans-2）がin vitro, in vivoにおいて特異的に胃癌に集積するという知見に基づきPET診断薬として利用可能なことを示すものである。
in vitro及びin vivoの実験とそのデータを以下に示す。
This example shows that the synthesized porphyrin derivative (ZnTFPP (SGlc) trans-2) can be used as a PET diagnostic agent based on the knowledge that it specifically accumulates in gastric cancer in vitro and in vivo. .
In vitro and in vivo experiments and their data are shown below.
(1)62Zn含有ポルフィリン誘導体の in vitro試験（細胞取り込み試験）
6 wellプレートにRGM-1, RGK-1細胞株を播種（1×106cells/well, 1.0 mL)し、37oC, 5% CO2インキュベータで終夜培養した。
15 mL遠沈管に10% FCS入り培地3430μLに実施例１で合成したポルフィリン化合物のDMSO溶液を70μL加え、添加溶液を調製した。この添加溶液を、1.5 mL/well (n = 3)ずつ6 wellプレートに暗所下で添加し、6 wellプレートを37oC, 5% CO2インキュベータで6時間薬剤（ZnTFPP(SGlc)cis-2, ZnTFPP(SGlc)trans-2）を接触させた。
薬剤濃度：4.5μM in 1% DMSO/10% FCS/培地, 62Zn濃度：3.0 kBq/well
薬剤接触後、各wellをPBS 1 mL×2で洗浄し、0.02% EDTA/0.25% trypsin in PBS (1:1)溶液を各wellに0.5 mL加え細胞をはがした。その後1% Triton-X 100 in PBSを加えた後、新しい15 mL遠沈管に各wellの溶液をうつし、細胞抽出液をシンチレータで測定した。
時間に対する薬剤の取り込み量を、亜鉛の同位体元素である64Znを導入した64Znポルフィリン誘導体(c = 0.5μM)、又は62Znを導入した62Znポルフィリン誘導体を用いて行った。その結果を図1、図2に示す。
64Zn-TFPP(SGlc)trans-2は薬剤接触12, 24時間後にガン細胞株(RGK-1)に特異的に取り込まれた（図１）。
放射核種(62Zn)の導入したポルフィリン誘導体（62Zn-TFPP(SGlc)trans-2）の細胞取り込み試験においても、図１と同様の結果が得られた（図２）。
(1) In vitro test of 62 Zn-containing porphyrin derivative (cell uptake test)
A 6-well plate was seeded with RGM-1, RGK-1 cell lines (1 × 10 6 cells / well, 1.0 mL) and cultured overnight in a 37 ° C., 5% CO 2 incubator.
In a 15 mL centrifuge tube, 70 μL of the DMSO solution of the porphyrin compound synthesized in Example 1 was added to 3430 μL of 10% FCS-containing medium to prepare an addition solution. This added solution was added to a 6-well plate at 1.5 mL / well (n = 3) in the dark, and the 6-well plate was added to the drug (ZnTFPP (SGlc) cis-) in a 37 ° C, 5% CO 2 incubator for 6 hours. 2, ZnTFPP (SGlc) trans-2) was contacted.
Drug concentration: 4.5 μM in 1% DMSO / 10% FCS / medium, 62 Zn concentration: 3.0 kBq / well
After contact with the drug, each well was washed with 1 mL × 2 PBS, and 0.5 mL of 0.02% EDTA / 0.25% trypsin in PBS (1: 1) solution was added to each well to peel off the cells. Thereafter, 1% Triton-X 100 in PBS was added, the solution in each well was transferred to a new 15 mL centrifuge tube, and the cell extract was measured with a scintillator.
The uptake of the drug over time, 64 Zn porphyrin derivatives obtained by introducing a 64 Zn is isotopes of zinc (c = 0.5μM), or 62 Zn was performed using 62 Zn porphyrin derivatives obtained by introducing a. The results are shown in FIGS.
64 Zn-TFPP (SGlc) trans-2 was specifically incorporated into the cancer cell line (RGK-1) 12 and 24 hours after drug contact (FIG. 1).
Also in cellular uptake test radionuclides (62 Zn) of the introduced porphyrin derivative (62 Zn-TFPP (SGlc) trans-2), the same result as Figure 1 was obtained (Fig. 2).
(2) 62Zn導入の動物試験（PET評価）
ナシ型フラスコに150μMの薬剤メタノール溶液を200μL分注し、62ZnCl2in NaClaq.を500μL (16 MBq/mL)を加えた。その後、ナスフラスコをあらかじめ滅菌したエバポレータを用い回転させながら10分間ドライヤーで加熱した後、溶媒留去した。その後、ナスフラスコにあらかじめ滅菌したEtOH:PEG400:water (2:3:5)を300μL加えたのち1.5 mLのエッペンチューブに溶液を移した。
(2) 62 Zn-introduced animal test (PET evaluation)
200 μL of a 150 μM drug methanol solution was dispensed into a pear-shaped flask, and 500 μL (16 MBq / mL) of 62 ZnCl 2 in NaClaq. Was added. Thereafter, the eggplant flask was heated with a dryer for 10 minutes while rotating using a pre-sterilized evaporator, and then the solvent was distilled off. Thereafter, 300 μL of pre-sterilized EtOH: PEG400: water (2: 3: 5) was added to the eggplant flask, and the solution was transferred to a 1.5 mL Eppendorf tube.
PET撮影
RGK-36細胞を左後肢に移植したヌードマウス(BALB/cSLC-nu/nu)に、62Znポルフィリンの溶液100μLを尾静脈投与した。
薬剤濃度：3μM in EtOH:PEG400:water (2:3:5), 62Zn濃度：4.0 kBq
薬剤投与1,3, 8, 24時間後、iPET/MRI装置を用いてマウスの全身のPET画像を撮影した。
その結果、薬剤投与8時間後までは、どちらの薬剤も肝臓や腸管に集積し、腫瘍へはほぼ集積していなかった。しかし24時間後では肝臓や腸管に高い集積（黄色）が見られたが、腫瘍部位にも薬剤が集積（赤色）した。投与3時間後と24時間後のPET画像を図3に示す。
PET photography
Nude mice (BALB / cSLC-nu / nu) transplanted with RGK-36 cells in the left hind limb were administered with 100 μL of 62 Zn porphyrin solution via the tail vein.
Drug concentration: 3 μM in EtOH: PEG400: water (2: 3: 5), 62 Zn concentration: 4.0 kBq
At 1, 3, 8, and 24 hours after drug administration, a PET image of the whole body of the mouse was taken using an iPET / MRI apparatus.
As a result, until 8 hours after drug administration, both drugs accumulated in the liver and intestinal tract, but almost no accumulation in the tumor. However, after 24 hours, high accumulation (yellow) was observed in the liver and intestinal tract, but the drug also accumulated (red) at the tumor site. The PET images 3 hours and 24 hours after administration are shown in FIG.
ポルフィリン化合物の合成
5-[4-(3-ヒドロキシエトキシ)-2,3,5,6-テトラフルオロフェニル]-10,15,20-トリス (2,3,4,5,6-ペンタフルオロフェニル)ポルフィリン (H21EG)
5-[4-(3-ヒドロキシエトキシ)-2,3,5,6- テトラフルオロフェニル]-10,15,20-tris(2,3,4,5,6-ペンタフルオロフェニル)ポルフィナート亜鉛 (II) (Zn1EG)
100 mLフラスコを三本用意し、一本当たり約200 mgのH2TFPPを加え、DMF 30 mLを加えた後、6当量のエチレングリコールとカリウム-t-ブトキシドを加えて-15℃で15分間反応させた。使用したH2TFPP総量613 mg (629μmol)、エチレングリコール総量210μL (3.78 mmol)、カリウム-t-ブトキシド総量は423 mg (3.78 mmol)、DMF 60 mLで反応を行い、反応後は反応溶液を合わせた。この反応溶液に、冷CH2Cl2 100 mL加え、冷水100 mLで5回分液した。有機層を無水Na2SO4で乾燥後、溶媒留去した。粗生成物をシリカゲルカラムクロマトグラフィー(CH2Cl2〜CH2Cl2 : EtOAc : acetone = 5 : 3 :3)で目的物を分離精製した後、フラッシュシリカゲルカラムクロマトグラフィー(CH2Cl2 : EtOAc = 7 : 3)で精製を行い、H21EGを収率15.3% (収量97.7 mg, 96.2μmol)、HPLC純度99%以上で得た。
得られたH21EGを100 mLフラスコに、酢酸亜鉛二水和物を5当量加えCH2Cl2 10 mLで溶解し、30℃で終夜撹拌した。その後、シリカゲルカラムクロマトグラフィー(CH2Cl2: EtOAc : hexane = 7 : 5 : 8)で精製し、Zn1EGを収率98.6%、HPLC純度99%以上で得た。化合物は、1H NMRのインナーピロールプロトンピークの消失とUV-visスペクトルにより亜鉛導入を確認した。
Synthesis of porphyrin compounds
5- [4- (3-hydroxyethoxy) -2,3,5,6-tetrafluorophenyl] -10,15,20-tris (2,3,4,5,6-pentafluorophenyl) porphyrin (H 2 1 EG )
5- [4- (3-hydroxyethoxy) -2,3,5,6-tetrafluorophenyl] -10,15,20-tris (2,3,4,5,6-pentafluorophenyl) porphinate zinc (II) (Zn1 EG )
Prepare three 100 mL flasks, add approximately 200 mg of H 2 TFPP, add 30 mL of DMF, add 6 equivalents of ethylene glycol and potassium-t-butoxide, and add 15 mL at -15 ° C for 15 minutes. Reacted. The total amount of H 2 TFPP used was 613 mg (629 μmol), the total amount of ethylene glycol was 210 μL (3.78 mmol), the total amount of potassium t-butoxide was 423 mg (3.78 mmol), and DMF 60 mL was used. It was. To this reaction solution, 100 mL of cold CH 2 Cl 2 was added, and the solution was separated 5 times with 100 mL of cold water. The organic layer was dried over anhydrous Na 2 SO 4 and evaporated. The crude product was purified by silica gel column chromatography was separated and purified desired product (CH 2 Cl 2 ~CH 2 Cl 2: EtOAc: acetone = 5:: 3 3), flash silica gel column chromatography (CH 2 Cl 2: EtOAc = 7: 3), and H 2 1 EG was obtained in a yield of 15.3% (yield 97.7 mg, 96.2 μmol) with an HPLC purity of 99% or more.
The resulting H 2 1 EG to 100 mL flask, zinc acetate dihydrate 5 was dissolved in an equivalent added CH 2 Cl 2 10 mL, and stirred overnight at 30 ° C.. Thereafter, the product was purified by silica gel column chromatography (CH 2 Cl 2 : EtOAc: hexane = 7: 5: 8) to obtain Zn1 EG with a yield of 98.6% and HPLC purity of 99% or more. The compound was confirmed to have zinc introduced by disappearance of the inner pyrrole proton peak of 1 H NMR and UV-vis spectrum.
H21EG; 1H NMR (500.16 MHz, CDCl3, Si(CH3)4= 0 ppm)δ(ppm)= 8.95 (2H, m,β-pyrroleH), 8.91 (6H, m,β-pyrroleH), 4.73 (2H, t, 3J= 4.5 Hz, CH2), 4.18 (2H, q, 3J= 4.5 Hz, OCH2) 2.26 (1H, t, CH2OH), -2.92 (2H, s, inner pyrroleH). 19F NMR (470.62 MHz, CDCl3, CF3CO2H= -76.50 ppm):δ(ppm)= -137.2 (6F, m, 2,6-PhF), -139.0 (2F, m, 2,6-PhFEG), -152.0 (3F, m, 4-PhF), -157.6 (2F, m, 3,5-PhFEG), -162.0 (6F, m, 3,5-PhF). 13C NMR (100.53 MHz, CDCl3, CDCl3= 77.00 ppm):δ(ppm)= 147.8, 145.3, 143.6, 142.1, 140.9, 139.6, 138.8, 136.3 (PhC), 131.2 (β-pyrroleC), 115.6 (1-PhC), 114.1 (1-PhCEG), 104.8 (meso-PhCEG), 103.5 (meso-PhC), 76.8 (-OCH2), 62.0 (CH2OH). ESI-MS (m/ z)= [M+Na+] calcd for C46H15F19N4O2Na, 1039.07893; found, 1039.07886. UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25°C):λ/nm(ε×10-3/M-1・cm-1) = 412 (369), 506 (28.4), 535 (5.51), 582 (9.37), 633 (1.75). H 2 1 EG ; 1 H NMR (500.16 MHz, CDCl 3 , Si (CH 3 ) 4 = 0 ppm) δ (ppm) = 8.95 (2H, m, β-pyrroleH), 8.91 (6H, m, β-pyrroleH ), 4.73 (2H, t, 3 J = 4.5 Hz, CH 2 ), 4.18 (2H, q, 3 J = 4.5 Hz, OCH 2 ) 2.26 (1H, t, CH 2 OH), -2.92 (2H, s 19 F NMR (470.62 MHz, CDCl 3 , CF 3 CO 2 H = -76.50 ppm): δ (ppm) = -137.2 (6F, m, 2,6-PhF), -139.0 (2F, m, 2,6-PhF EG ), -152.0 (3F, m, 4-PhF), -157.6 (2F, m, 3,5-PhF EG ), -162.0 (6F, m, 3,5-PhF) 13 C NMR (100.53 MHz, CDCl 3 , CDCl 3 = 77.00 ppm): δ (ppm) = 147.8, 145.3, 143.6, 142.1, 140.9, 139.6, 138.8, 136.3 (PhC), 131.2 (β-pyrroleC), 115.6 (1-PhC), 114.1 (1-PhC EG ), 104.8 (meso-PhC EG ), 103.5 (meso-PhC), 76.8 (-OCH 2 ), 62.0 (CH 2 OH). ESI-MS (m / z ) = [M + Na + ] calcd for C 46 H 15 F 19 N 4 O 2 Na, 1039.07893; found, 1039.07886.UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 -3 / M -1cm -1 ) = 412 (369), 506 (28.4), 535 (5.51), 582 (9.37), 633 (1.75).
Zn1EG; 1H NMR (399.65 MHz, acetone-d6, (CD3)2CO = 2.05 ppm):δ(ppm)= 9.25-9.22 (8H, m,β-pyrroleH), 4.69 (2H, t, 3J= 4.6 Hz, OCH2), 4.11 (2H, q, 3J= 5.5 Hz, CH2OH). UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25°C):λ/nm(ε×10-3/M-1・cm-1) = 422 (434), 507 (4.42), 553 (18.1). Zn1 EG ; 1 H NMR (399.65 MHz, acetone-d 6 , (CD 3 ) 2 CO = 2.05 ppm): δ (ppm) = 9.25-9.22 (8H, m, β-pyrroleH), 4.69 (2H, t, 3 J = 4.6 Hz, OCH 2 ), 4.11 (2H, q, 3 J = 5.5 Hz, CH 2 OH) .UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 -3 / M -1cm -1 ) = 422 (434), 507 (4.42), 553 (18.1).
5,15-トリス [4-(3-ヒドロキシエトキシ)-2,3,5,6-テトラフルオロフェニル]-10,20-(2,3,4,5,6-ペンタフルオロフェニル) ポルフィリン(H2trans-2EG)
5,10-トリス [4-(3-ヒドロキシエトキシ)-2,3,5,6-テトラフルオロフェニル]-15,20-(2,3,4,5,6-ペンタフルオロフェニル)ポルフィリン (H2cis-2EG)
5,10,15-トリス [4-(3-ヒドロキシエトキシ)-2,3,5,6-テトラフルオロフェニル]-20-(2,3,4,5,6-ペンタフルオロフェニル)ポルフィリン(H23EG)
5,15-トリス [4-(3-ヒドロキシエトキシ)-2,3,5,6-テトラフルオロフェニル]-10,20-(2,3,4,5,6-ペンタフルオロフェニル)ポルフィナート亜鉛(Zntrans-2EG)
5,10-トリス [4-(3-ヒドロキシエトキシ)-2,3,5,6-テトラフルオロフェニル]-15,20-(2,3,4,5,6-ペンタフルオロフェニル)ポルフィナート亜鉛(II) (Zncis-2EG)
5,10,15-トリス [4-(3-ヒドロキシエトキシ)-2,3,5,6-テトラフルオロフェニル]-20-(2,3,4,5,6-ペンタフルオロフェニル)ポルフィナート亜鉛(II) (Zn3EG)
H2TFPP総量1.252 g (1.29 mmol)、エチレングリコール総量575μL (10.32 mmol)、カリウム-t-ブトキシド総量は1.158 g (10.32 mmol)、DMF 60 mLを用いてH21EGと同様の実験を行い、粗生成物をシリカゲルカラムクロマトグラフィー(CH2Cl2〜CH2Cl2 : EtOAc : acetone = 5 : 3 :3)で目的物を分離精製した後、フラッシュシリカゲルカラムクロマトグラフィー(CH2Cl2 : EtOAc = 7 : 3 (H2trans-2EG, H2trans-2EG), CH2Cl2 : EtOAc : acetone = 5 : 3 :3 (H23EG))で精製を行い、H2trans-2EGを収率3.0% (収量40.7 mg, 38.5μmol)、HPLC純度96%、H2cis-2EGを収率9.7% (収量132 mg, 125μmol)、HPLC純度99%、またH23EGを収率35.8% (収量506 mg, 460μmol)、HPLC純度99%で得た。Zn1EGと同様の方法を用い、これらのポルフィリンに亜鉛を導入しシリカゲルカラムクロマトグラフィー(CH2Cl2: EtOAc : hexane = 5 : 2 : 3)で精製し、Zntrans-2EGを収率63.5% HPLC純度96%、またZncis-2EGを収率59.3% HPLC純度99%、Zn3EGを収率52.9% HPLC純度97%で得た。
5,15-Tris [4- (3-hydroxyethoxy) -2,3,5,6-tetrafluorophenyl] -10,20- (2,3,4,5,6-pentafluorophenyl) porphyrin (H 2 trans-2 EG )
5,10-Tris [4- (3-hydroxyethoxy) -2,3,5,6-tetrafluorophenyl] -15,20- (2,3,4,5,6-pentafluorophenyl) porphyrin (H 2 cis-2 EG )
5,10,15-tris [4- (3-hydroxyethoxy) -2,3,5,6-tetrafluorophenyl] -20- (2,3,4,5,6-pentafluorophenyl) porphyrin (H 2 3 EG )
5,15-Tris [4- (3-hydroxyethoxy) -2,3,5,6-tetrafluorophenyl] -10,20- (2,3,4,5,6-pentafluorophenyl) porphinate zinc (Zntrans-2 EG )
5,10-tris [4- (3-hydroxyethoxy) -2,3,5,6-tetrafluorophenyl] -15,20- (2,3,4,5,6-pentafluorophenyl) porphinate zinc (II) (Zncis-2 EG )
5,10,15-tris [4- (3-hydroxyethoxy) -2,3,5,6-tetrafluorophenyl] -20- (2,3,4,5,6-pentafluorophenyl) porphinate zinc (II) (Zn3 EG )
H 2 TFPP total amount 1.252 g (1.29 mmol), ethylene glycol total amount 575 μL (10.32 mmol), potassium-t-butoxide total amount 1.158 g (10.32 mmol), DMF 60 mL was used to perform the same experiment as H 2 EG. the crude product was purified by silica gel column chromatography was separated and purified desired product (CH 2 Cl 2 ~CH 2 Cl 2: EtOAc: acetone = 5:: 3 3), flash silica gel column chromatography (CH 2 Cl 2: Purification with EtOAc = 7: 3 (H 2 trans-2 EG , H 2 trans-2 EG ), CH 2 Cl 2 : EtOAc: acetone = 5: 3: 3 (H 2 3 EG )) and H 2 trans -2 EG yield 3.0% (yield 40.7 mg, 38.5 μmol), HPLC purity 96%, H 2 cis-2 EG yield 9.7% (yield 132 mg, 125 μmol), HPLC purity 99%, and H 2 3 EG was obtained with a yield of 35.8% (yield 506 mg, 460 μmol) and HPLC purity of 99%. Using the same method as Zn1 EG , zinc was introduced into these porphyrins and purified by silica gel column chromatography (CH 2 Cl 2 : EtOAc: hexane = 5: 2: 3) to obtain Zntrans-2 EG in a yield of 63.5% An HPLC purity of 96%, a Zncis-2 EG yield of 59.3%, an HPLC purity of 99%, and a Zn3 EG yield of 52.9%, an HPLC purity of 97% were obtained.
H2cis-2EG; 1H NMR (500.16 MHz, CDCl3, Si(CH3)4= 0 ppm)δ(ppm)= 8.94 (4H, m,β-pyrroleH), 8.90 (4H, m,β-pyrroleH), 4.73 (4H, t, 3J= 4.5 Hz, CH2), 4.17 (4H, q, 3J= 4.5 Hz, OCH-2) 2.32 (2H, t, CH2OH), -2.92 (2H, s, inner pyrroleH). 1H NMR (500.16 MHz, C6D6, C6D6= 7.16 ppm):δ(ppm)= 8.87 (2H, d, 3J= 2.0 Hz, CH), 8.80 (2H, s, CH), 8.71 (2H, s, CH), 8.66 (2H, d, 3J= 2.0Hz, CH), 4.12(4H, t, 3J= 5.0 Hz, CH2), 3.53(4H, q, 3J= 5.0 Hz, CH2OH), 1.41(2H, t, 3J= 6.0 Hz, CH2OH), -3.22 (2H, s, inner pyrroleH). 19F NMR (470.62 MHz, CDCl3, CF3CO2H= -76.50 ppm):δ(ppm) = -137.2 (4F, m, 2,6-PhF), -139.0 (4F, m, 2,6-PhFEG), -152.1 (2F, m, 4-PhF), -157.7 (4F, m, 3,5-PhFEG), -162.1 (4F, m, 3,5-PhF). 13C NMR (100.53 MHz, CDCl3, CDCl3= 77.00 ppm):δ(ppm)= 147.8, 145.3, 143.6, 142.1, 140.9, 139.6, 138.8, 136.3 (PhC), 131.2 (β-pyrroleC), 115.6 (1-PhC), 114.1 (1-PhCEG), 104.6 (meso-PhCEG), 103.2 (meso-PhC), 76.8 (-OCH2), 62.0 (CH2OH). 13C NMR (100.53 MHz, CD3OD, CD3OD= 49.0 ppm):δ(ppm)= 146.9, 145.1, 143.9, 142.6, 141.3, 140.6, 139.5, 138.0, 135.9 (PhC), 129.6 (β-pyrroleC), 116.8 (1-PhC), 114.8 (1-PhCEG), 106.1 (meso-PhCEG), 104.6 (meso-PhC), 78.0 (-OCH2), 62.5 (CH2OH). ESI-MS (m/ z)= [M+Na+] calcd for C48H20F18N4O4Na, 1081.10948; found, 1081.10953. UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25°C):λ/nm(ε×10-3/M-1・cm-1) = 413 (373), 506 (27.9), 535 (5.27), 581 (9.20), 632 (1.63). H 2 cis-2 EG ; 1 H NMR (500.16 MHz, CDCl 3 , Si (CH 3 ) 4 = 0 ppm) δ (ppm) = 8.94 (4H, m, β-pyrroleH), 8.90 (4H, m, β -pyrroleH), 4.73 (4H, t, 3 J = 4.5 Hz, CH 2 ), 4.17 (4H, q, 3 J = 4.5 Hz, OCH- 2 ) 2.32 (2H, t, CH 2 OH), -2.92 ( 1 H NMR (500.16 MHz, C 6 D 6 , C 6 D 6 = 7.16 ppm): δ (ppm) = 8.87 (2H, d, 3 J = 2.0 Hz, CH), 8.80 (2H, s, CH), 8.71 (2H, s, CH), 8.66 (2H, d, 3 J = 2.0Hz, CH), 4.12 (4H, t, 3 J = 5.0 Hz, CH 2 ), 3.53 ( 4H, q, 3 J = 5.0 Hz, CH 2 OH), 1.41 (2H, t, 3 J = 6.0 Hz, CH 2 OH), -3.22 (2H, s, inner pyrroleH). 19 F NMR (470.62 MHz, CDCl 3 , CF 3 CO 2 H = -76.50 ppm): δ (ppm) = -137.2 (4F, m, 2,6-PhF), -139.0 (4F, m, 2,6-PhF EG ), -152.1 (2F, m, 4-PhF), -157.7 (4F, m, 3,5-PhF EG ), -162.1 (4F, m, 3,5-PhF). 13 C NMR (100.53 MHz, CDCl 3 , CDCl 3 = 77.00 ppm): δ (ppm) = 147.8, 145.3, 143.6, 142.1, 140.9, 139.6, 138.8, 136.3 (PhC), 131.2 (β-pyrroleC), 115.6 (1-PhC), 114.1 (1-PhC EG ), 104.6 (meso-PhC EG ), 103.2 (meso-PhC), 76.8 (-OCH 2 ), 62.0 (CH 2 OH). 13 C NMR (100. 53 MHz, CD 3 OD, CD 3 OD = 49.0 ppm): δ (ppm) = 146.9, 145.1, 143.9, 142.6, 141.3, 140.6, 139.5, 138.0, 135.9 (PhC), 129.6 (β-pyrroleC), 116.8 ( 1-PhC), 114.8 (1-PhC EG ), 106.1 (meso-PhC EG ), 104.6 (meso-PhC), 78.0 (-OCH 2 ), 62.5 (CH 2 OH). ESI-MS (m / z) = [M + Na + ] calcd for C 48 H 20 F 18 N 4 O 4 Na, 1081.10948; found, 1081.10953.UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 -3 / M -1cm -1 ) = 413 (373), 506 (27.9), 535 (5.27), 581 (9.20), 632 (1.63).
Zncis-2EG; 1H NMR (399.65 MHz, acetone-d6, (CD3)2CO = 2.05 ppm):δ(ppm)= 9.17-9.14 (8H, m,β-pyrroleH), 4.61 (4H, t, 3J= 4.5 Hz, OCH2), 4.00 (4H, q, 3J= 5.1 Hz, CH2OH). UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25°C):λ/nm(ε×10-3/M-1・cm-1) = 422 (434), 507 (4.42), 553 (18.1). Zncis-2 EG ; 1 H NMR (399.65 MHz, acetone-d 6 , (CD 3 ) 2 CO = 2.05 ppm): δ (ppm) = 9.17-9.14 (8H, m, β-pyrroleH), 4.61 (4H, t, 3 J = 4.5 Hz, OCH 2 ), 4.00 (4H, q, 3 J = 5.1 Hz, CH 2 OH) .UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25 ° C) : λ / nm (ε × 10 -3 / M -1cm -1 ) = 422 (434), 507 (4.42), 553 (18.1).
H2trans-2EG; 1H NMR (500.16 MHz, CDCl3, Si(CH3)4= 0 ppm):δ(ppm)= 8.96 (4H, m,β-pyrroleH), 8.91 (4H, m,β-pyrroleH), 4.72 (4H, t, 3J= 4.5 Hz, CH2), 4.17 (4H, q, 3J= 4.5 Hz, OCH-2) 2.35 (2H, t, CH2OH), -2.92 (2H, s, inner pyrroleH). 1H NMR (500.16 MHz, C6D6, C6D6= 7.16 ppm):δ(ppm)= 8.86 (4H, d, 3J= 2.5 Hz, CH), 8.66 (4H, d, 3J= 2.5Hz, CH), 4.12(4H, t, 3J= 4.0 Hz, CH2), 3.53(4H, q, 3J= 4.0 Hz, CH2OH), 1.38(2H, t, 3J= 6.0 Hz, CH2OH), -3.21 (2H, s, inner pyrroleH). 19F NMR (470.62 MHz, CDCl3, CF3CO2H= -76.50 ppm):δ(ppm) = -137.2 (4F, m, 2,6-PhF), -139.0 (4F, m, 2,6-PhFEG), -152.1 (2F, m, 4-PhF), -157.7 (4F, m, 3,5-PhFEG), -162.1 (4F, m, 3,5-PhF). 13C NMR (100.53 MHz, CD3OD, CD3OD= 49.0 ppm):δ(ppm)= 146.9, 145.1, 143.9, 142.6, 141.3, 140.6, 139.5, 138.0, 135.9 (PhC), 129.6 (β-pyrroleC), 116.8 (1-PhC), 114.8 (1-PhCEG), 106.0 (meso-PhCEG), 104.7 (meso-PhC), 78.0 (-OCH2), 62.5 (CH2OH). ESI-MS (m/ z)= [M+Na+] calcd for C48H20F18N4O4Na, 1081.10948; found, 1081.10988. UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25°C):λ/nm(ε×10-3/M-1・cm-1) = 413 (333), 506 (24.9), 535 (4.85), 581 (8.14), 632 (1.41). H 2 trans-2 EG ; 1 H NMR (500.16 MHz, CDCl 3 , Si (CH 3 ) 4 = 0 ppm): δ (ppm) = 8.96 (4H, m, β-pyrroleH), 8.91 (4H, m, β-pyrroleH), 4.72 (4H, t, 3 J = 4.5 Hz, CH 2 ), 4.17 (4H, q, 3 J = 4.5 Hz, OCH- 2 ) 2.35 (2H, t, CH 2 OH), -2.92 (2H, s, inner pyrroleH). 1 H NMR (500.16 MHz, C 6 D 6 , C 6 D 6 = 7.16 ppm): δ (ppm) = 8.86 (4H, d, 3 J = 2.5 Hz, CH), 8.66 (4H, d, 3 J = 2.5Hz, CH), 4.12 (4H, t, 3 J = 4.0 Hz, CH 2 ), 3.53 (4H, q, 3 J = 4.0 Hz, CH 2 OH), 1.38 ( 2H, t, 3 J = 6.0 Hz, CH 2 OH), -3.21 (2H, s, inner pyrroleH). 19 F NMR (470.62 MHz, CDCl 3 , CF 3 CO 2 H = -76.50 ppm): δ (ppm ) = -137.2 (4F, m, 2,6-PhF), -139.0 (4F, m, 2,6-PhF EG ), -152.1 (2F, m, 4-PhF), -157.7 (4F, m, . 3,5-PhF EG), -162.1 (4F, m, 3,5-PhF) 13 C NMR (100.53 MHz, CD 3 OD, CD 3 OD = 49.0 ppm): δ (ppm) = 146.9, 145.1, 143.9, 142.6, 141.3, 140.6, 139.5, 138.0, 135.9 (PhC), 129.6 (β-pyrroleC), 116.8 (1-PhC), 114.8 (1-PhC EG ), 106.0 (meso-PhC EG ), 104.7 (meso -PhC), 78.0 (-OCH 2 ), 62.5 (CH 2 OH). ESI-MS (m / z) = [M + Na + ] calcd for C 48 H 20 F 18 N 4 O 4 Na, 1081.10948; found, 1081.10988.UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 -3 / M -1・ Cm -1 ) = 413 (333), 506 (24.9), 535 (4.85), 581 (8.14), 632 (1.41).
Zntrans-2EG; 1H NMR (399.65 MHz, acetone-d6, (CD3)2CO = 2.05 ppm):δ(ppm)= 9.18-9.14 (8H, m,β-pyrroleH), 4.60 ppm (4H, t, 3J= 4.8 Hz, OCH2), 4.00 ppm (4H, q, 3J= 5.1 Hz, CH2OH). UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25°C): λ/nm(ε×10-3/M-1・cm-1) = 423 (579), 508 (2.88), 553 (25.6).
H23EG; 1H NMR (500.16 MHz, CDCl3, Si(CH3)4= 0 ppm):δ(ppm)= 8.94 (6H, m,β-pyrroleH), 8.90 (2H, m,β-pyrroleH), 4.72 (6H, t, 3J= 4.5 Hz, CH2), 4.17 (6H, q, 3J= 4.5 Hz, OCH2) 2.34 (3H, t, CH2OH), -2.92 (2H, s, inner pyrroleH). 1H NMR (500.16 MHz, (CD3)2CO, (CD3)2CO = 2.05 ppm)δ(ppm)= 9.61-9.02 (8H, m,β-pyrroleH), 4.70 (6H, t, 3J= 5.5 Hz, CH2), 4.10 (6H, q, 3J= 5.5 Hz, CH2OH).
19F NMR (470.62 MHz, CDCl3, CF3CO2H= -76.50 ppm):δ(ppm) = -137.2 (2F, m, 3,5-PhF), -139.0 (6F, m, 2,6-PhFEG), -152.2 (1F, m, 4-PhF), -157.7 (6F, m, 3,5-PhFEG), -162.1 (2F, m, 2,6-PhF). 19F NMR (470.62 MHz, (CD3)2CO, CF3CO2H= -76.50 ppm)δ(ppm) = -139.4 (2F, m, 2,6-PhF), -141.5 (6F, m, 2,6-PhFEG), -155.0 (1F, m, 4-PhF), -158.3 (6F, m, 3,5-PhFEG), -164.0 (2F, m, 3,5-PhF).
13C NMR (100.53 MHz, CD3OD, CD3OD= 49.0 ppm):δ(ppm)= 146.9, 145.1, 143.9, 142.6, 141.3, 140.6, 139.5, 138.0, 135.9 (PhC), 129.6 (β-pyrroleC), 114.9 (1-PhCEG), 105.8 (meso-PhCEG), 104.5 (meso-PhC), 78.0 (-OCH2), 62.5 (CH2OH). ESI-MS (m/ z)= [M+Na+] calcd for C50H25F17N4O6Na, 1123.14003; found, 1123.13974. UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25°C): λ/nm(ε×10-3/M-1・cm-1) = 414 (322), 506 (23.9), 535 (4.90), 581 (7.96), 633 (1.48).
Zntrans-2 EG ; 1 H NMR (399.65 MHz, acetone-d 6 , (CD 3 ) 2 CO = 2.05 ppm): δ (ppm) = 9.18-9.14 (8H, m, β-pyrroleH), 4.60 ppm (4H , t, 3 J = 4.8 Hz, OCH 2 ), 4.00 ppm (4H, q, 3 J = 5.1 Hz, CH 2 OH) .UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 -3 / M -1cm -1 ) = 423 (579), 508 (2.88), 553 (25.6).
H 2 3 EG ; 1 H NMR (500.16 MHz, CDCl 3 , Si (CH 3 ) 4 = 0 ppm): δ (ppm) = 8.94 (6H, m, β-pyrroleH), 8.90 (2H, m, β- pyrroleH), 4.72 (6H, t, 3 J = 4.5 Hz, CH 2 ), 4.17 (6H, q, 3 J = 4.5 Hz, OCH 2 ) 2.34 (3H, t, CH 2 OH), -2.92 (2H, 1 H NMR (500.16 MHz, (CD 3 ) 2 CO, (CD 3 ) 2 CO = 2.05 ppm) δ (ppm) = 9.61-9.02 (8H, m, β-pyrroleH), 4.70 ( 6H, t, 3 J = 5.5 Hz, CH 2 ), 4.10 (6H, q, 3 J = 5.5 Hz, CH 2 OH).
19 F NMR (470.62 MHz, CDCl 3 , CF 3 CO 2 H = -76.50 ppm): δ (ppm) = -137.2 (2F, m, 3,5-PhF), -139.0 (6F, m, 2,6 -PhF EG ), -152.2 (1F, m, 4-PhF), -157.7 (6F, m, 3,5-PhF EG ), -162.1 (2F, m, 2,6-PhF). 19 F NMR ( 470.62 MHz, (CD 3 ) 2 CO, CF 3 CO 2 H = -76.50 ppm) δ (ppm) = -139.4 (2F, m, 2,6-PhF), -141.5 (6F, m, 2,6- PhF EG ), -155.0 (1F, m, 4-PhF), -158.3 (6F, m, 3,5-PhF EG ), -164.0 (2F, m, 3,5-PhF).
13 C NMR (100.53 MHz, CD 3 OD, CD 3 OD = 49.0 ppm): δ (ppm) = 146.9, 145.1, 143.9, 142.6, 141.3, 140.6, 139.5, 138.0, 135.9 (PhC), 129.6 (β-pyrroleC ), 114.9 (1-PhC EG ), 105.8 (meso-PhC EG ), 104.5 (meso-PhC), 78.0 (-OCH 2 ), 62.5 (CH 2 OH). ESI-MS (m / z) = (M + Na + ] calcd for C 50 H 25 F 17 N 4 O 6 Na, 1123.14003; found, 1123.13974.UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm ( ε × 10 -3 / M -1cm -1 ) = 414 (322), 506 (23.9), 535 (4.90), 581 (7.96), 633 (1.48).
Zn3EG; 1H NMR (399.65 MHz, acetone-d6, (CD3)2CO = 2.05 ppm):δ(ppm)= 9.24 (8H, m,β-pyrroleH), 4.62 ppm (4H, t, 3J= 5.1 Hz, OCH2), 4.02 ppm (4H, q, 3J= 4.9 Hz, CH2OH). UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25°C): λ/nm(ε×10-3/M-1・cm-1) = 423 (483), 508 (2.42), 553 (2.10). Zn3 EG ; 1 H NMR (399.65 MHz, acetone-d 6 , (CD 3 ) 2 CO = 2.05 ppm): δ (ppm) = 9.24 (8H, m, β-pyrroleH), 4.62 ppm (4H, t, 3 J = 5.1 Hz, OCH 2 ), 4.02 ppm (4H, q, 3 J = 4.9 Hz, CH 2 OH) .UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 -3 / M -1cm -1 ) = 423 (483), 508 (2.42), 553 (2.10).
5,10,15,20-テトラキス [4-(3-ヒドロキシエトキシ)-2,3,5,6-テトラフルオロフェニル] ポルフィリン (H24EG)
5,10,15,20-テトラキス [4-(3-ヒドロキシエトキシ)-2,3,5,6-テトラフルオロフェニル] ポルフィナート亜鉛(II) (Zn4EG)
H2TFPP総量234 mg (240μmol)、エチレングリコール総量120μL (2.16 mmol)、カリウム-t-ブトキシド総量は242 mg (10.32 mmol)、DMF 60 mLを用いてH21EGと同様の実験を行い、粗生成物をシリカゲルカラムクロマトグラフィー(CH2Cl2〜CH2Cl2 : EtOAc : acetone = 5 : 3 :3)で目的物を分離精製した後、フラッシュシリカゲルカラムクロマトグラフィー(CH2Cl2 : EtOAc : acetone = 5 : 3 :3)で精製を行い、H24EGを収率11.2% (収量26.9 mg, 23.6μmol)、HPLC純度96%で得た。Zn1EGと同様の方法を用い、これらのポルフィリンに亜鉛を導入しシリカゲルカラムクロマトグラフィー(CH2Cl2: EtOAc : acetone = 5 : 3 :3)で精製し、Zn4EGを収率35.0% HPLC純度95%で得た。
H24EG; 1H NMR (500.16 MHz, CDCl3, Si(CH3)4= 0 ppm)δ(ppm)= 8.93 (8H, s,β-pyrroleH), 4.72(8H, t, 4J= 4.5 Hz, CH2), 4.17 (8H, q, 4J= 4.5 Hz, OCH-2), 2.32 (4H, t, CH2OH), -2.92 (2H, s, inner pyrroleH). 19F NMR (470.62 MHz, (CD3)2CO, CF3CO2H= -76.50 ppm)δ(ppm) = -141.5 (8F, m, 2,6-PhFEG), -158.3 (8F, m, 3,5-PhFEG). 13C NMR (100.53 MHz, CD3OD, CD3OD= 49.0 ppm):δ(ppm)= 146.9, 145.1, 143.9, 142.6, 141.3, 140.6, 139.5, 138.0, 135.9 (PhC), 129.6 (β-pyrroleC), 114.9 (1-PhCEG), 105.7 (meso-PhCEG), 78.0 (-OCH2), 62.5 (CH2OH). ESI-MS(m/z)= [M+Na+] calcd for C52H30F16N4O8Na, 1165.17058; found, 1165.18026. UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25°C): λ/nm(ε×10-3/M-1・cm-1) = 414 (419), 507 (30.4), 535 (6.20), 581 (9.95), 633 (1.67).
5,10,15,20-Tetrakis [4- (3-hydroxyethoxy) -2,3,5,6-tetrafluorophenyl] porphyrin (H 2 4 EG )
5,10,15,20-Tetrakis [4- (3-hydroxyethoxy) -2,3,5,6-tetrafluorophenyl] porphinate zinc (II) (Zn4 EG )
H 2 TFPP total amount 234 mg (240 μmol), ethylene glycol total amount 120 μL (2.16 mmol), potassium-t-butoxide total amount 242 mg (10.32 mmol), DMF 60 mL was used, the same experiment as H 2 1 EG was performed, the crude product was purified by silica gel column chromatography was separated and purified desired product (CH 2 Cl 2 ~CH 2 Cl 2: EtOAc: acetone = 5:: 3 3), flash silica gel column chromatography (CH 2 Cl 2: EtOAc : Acetone = 5: 3: 3), and H 2 4 EG was obtained in a yield of 11.2% (yield 26.9 mg, 23.6 μmol) with an HPLC purity of 96%. Using the same method as Zn1 EG , zinc was introduced into these porphyrins and purified by silica gel column chromatography (CH 2 Cl 2 : EtOAc: acetone = 5: 3: 3) to obtain Zn4 EG with a 35.0% HPLC purity. Obtained at 95%.
H 2 4 EG ; 1 H NMR (500.16 MHz, CDCl 3 , Si (CH 3 ) 4 = 0 ppm) δ (ppm) = 8.93 (8H, s, β-pyrroleH), 4.72 (8H, t, 4 J = 4.5 Hz, CH 2 ), 4.17 (8H, q, 4 J = 4.5 Hz, OCH- 2 ), 2.32 (4H, t, CH 2 OH), -2.92 (2H, s, inner pyrroleH). 19 F NMR ( 470.62 MHz, (CD 3 ) 2 CO, CF 3 CO 2 H = -76.50 ppm) δ (ppm) = -141.5 (8F, m, 2,6-PhF EG ), -158.3 (8F, m, 3,5 . -PhF EG) 13 C NMR ( 100.53 MHz, CD 3 OD, CD 3 OD = 49.0 ppm): δ (ppm) = 146.9, 145.1, 143.9, 142.6, 141.3, 140.6, 139.5, 138.0, 135.9 (PhC), 129.6 (β-pyrroleC), 114.9 (1-PhC EG ), 105.7 (meso-PhC EG ), 78.0 (-OCH 2 ), 62.5 (CH 2 OH). ESI-MS (m / z) = (M + Na + ] calcd for C 52 H 30 F 16 N 4 O 8 Na, 1165.17058; found, 1165.18026.UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10-3 / M- 1cm - 1 ) = 414 (419), 507 (30.4), 535 (6.20), 581 (9.95), 633 (1.67).
Zn4EG; 1H NMR (399.65 MHz, acetone-d6, (CD3)2CO = 2.05 ppm):δ(ppm)= 9.12 (8H, brs,β-pyrroleH), 4.62 ppm (4H, t, 3J= 5.1 Hz, OCH2), 4.00 ppm (4H, q, 3J= 5.0 Hz, CH2OH). UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25°C):λ/nm(ε×10-3/M-1・cm-1) = 424 (764), 508 (5.19), 553 (34.7). Zn4 EG ; 1 H NMR (399.65 MHz, acetone-d 6 , (CD 3 ) 2 CO = 2.05 ppm): δ (ppm) = 9.12 (8H, brs, β-pyrroleH), 4.62 ppm (4H, t, 3 J = 5.1 Hz, OCH 2 ), 4.00 ppm (4H, q, 3 J = 5.0 Hz, CH 2 OH) .UV-vis (c = 5.00μM, DMSO, path length = 1 cm, 25 ° C): λ / nm (ε × 10 -3 / M -1cm -1 ) = 424 (764), 508 (5.19), 553 (34.7).
ZnTFPP-OCH2CCH (Zn1propa)
100 mLフラスコにZnTFPP (96.8 mg, 93.1μmol)、propargylalchol (5.43μL, 93.3μmol)とK2CO3 (106.3 mg, 745μmol)をDMSO 30 mLを50℃で15時間加熱撹拌した。この反応溶液に、冷CH2Cl2 100 mL加え、冷水100 mLで5回分液した。有機層を無水Na2SO4で乾燥後、溶媒留去した。粗生成物をシリカゲルカラムクロマトグラフィー(CH2Cl2 : hexane = 20:80 - 50:50)で目的物の分離精製を行い、Zn1propaを収率13%で得た。
1H NMR (500.16 MHz, CDCl3, Si(CH3)4= 0 ppm):δ(ppm)= 9.05-9.04 (2H, m,β-pyrroleH), 9.01-9.00 (6H, m,β-pyrroleH), 5.22 (2H, d, 3J= 2.47 Hz, CH2), 2.81 (1H, t, 3J= 2.47 Hz, CCH). 19F NMR (470.62 MHz, CDCl3, CF3CO2H= -76.50 ppm):δ(ppm)= -136.65 (2F, m, 3,5-PhF), -138.46 (2F, t, 2,6-PhFpropa), -151.81 (1F, m, 4-PhF), -155.63 (2F, m, 3,5-PhFpropa), -161.60 (2F, m, 2,6-PhF).
ZnTFPP-OCH 2 CCH (Zn1 propa )
ZnTFPP (96.8 mg, 93.1 μmol), propargylalchol (5.43 μL, 93.3 μmol) and K 2 CO 3 (106.3 mg, 745 μmol) and DMSO 30 mL were heated and stirred at 50 ° C. for 15 hours in a 100 mL flask. To this reaction solution, 100 mL of cold CH 2 Cl 2 was added, and the solution was separated 5 times with 100 mL of cold water. The organic layer was dried over anhydrous Na 2 SO 4 and evaporated. The crude product was separated and purified by silica gel column chromatography (CH 2 Cl 2 : hexane = 20 : 80-50: 50) to obtain Zn1 propa in a yield of 13%.
1 H NMR (500.16 MHz, CDCl 3 , Si (CH 3 ) 4 = 0 ppm): δ (ppm) = 9.05-9.04 (2H, m, β-pyrroleH), 9.01-9.00 (6H, m, β-pyrroleH ), 5.22 (2H, d, 3 J = 2.47 Hz, CH 2 ), 2.81 (1H, t, 3 J = 2.47 Hz, CCH). 19 F NMR (470.62 MHz, CDCl 3 , CF 3 CO 2 H =- 76.50 ppm): δ (ppm) = -136.65 (2F, m, 3,5-PhF), -138.46 (2F, t, 2,6-PhF propa ), -151.81 (1F, m, 4-PhF), -155.63 (2F, m, 3,5-PhF propa ), -161.60 (2F, m, 2,6-PhF).
ZnTFPP-triazole-TEG-FA
50 mLナスフラスコにZn1propa (34.5 mg, 32.2μmol)とテトラエチレングリコールアジドを連結した葉酸誘導体(FA-TEG-N3, 45.8 mg, ca. 1eq.)をDMF 20 mLに溶解させ、減圧脱気しアルゴン置換した。この溶液に臭化銅(11.2 mg, 78.1μmol)とN,N,N’,N”,N”-ペンタメチルジエチレントリアミン(PMDETA, 13.5μL, 64.3μmol)を加えアルゴン雰囲気下、室温で48時間撹拌した。この反応溶液に、冷CH2Cl2 100 mL加え、飽和食塩水100 mLで1回、水100 mLで3回分液した。有機層を無水Na2SO4で乾燥後、溶媒留去した。粗生成物をフラッシュカラムクロマトグラフィー(CH2Cl2 : MeOH = 1:0 - 4:1)で目的物の分離を行い、葉酸連結ポルフィリン(ZnTFPP-triazole-TEG-FA)を収率2.4%, HPLC純度97%で得た。
1H NMR (600.17MHz, acetone-d6, (CD3)2CO = 2.05 ppm):δ(ppm)=9.26-9.19 (9H, m,β-pyrroleH + pteridineC7H), 7.78-7.64 (5H, m, Ph-CONH + CH2CONHCH2 + 2-PhH ), 6.99-6.36 (3H, m, pteridineNH + pteridineC6-CH2NH-Ph +3-PhH), 5.72 (2H, m, propargylCH2), 4.71-3.99 (4H, m, pteridineC6-CH2NH-Ph + NHCH), 3.65-3.32 (16H, m, NHCH2CH2O, CH2CH2O, OCH2, CH2CH2N3), 2.37-0.83 (4H, m, CHCH2CH2, CH2CONH). 19F NMR (470.62 MHz, acetone-d6, CF3CO2H= -76.50 ppm):δ(ppm)= -140.63 (2F, m, 3,5-PhF), -142.38 (2F, m, 2,6-PhFtriazole-TEG-FA), -157.16 (1F, m, 4-PhF), -158.68 (2F, m, 3,5-PhFtriazole-TEG-FA), -165.89 (2F, m, 2,6-PhF).
ZnTFPP-triazole-TEG-FA
Dissolve folic acid derivative (FA-TEG-N 3 , 45.8 mg, ca. 1 eq.) Conjugated with Zn1propa (34.5 mg, 32.2 μmol) and tetraethyleneglycol azide in DMF 20 mL in a 50 mL eggplant flask and vacuum degassing And replaced with argon. To this solution, copper bromide (11.2 mg, 78.1 μmol) and N, N, N ', N ”, N” -pentamethyldiethylenetriamine (PMDETA, 13.5 μL, 64.3 μmol) were added and stirred at room temperature for 48 hours under an argon atmosphere. did. To this reaction solution, 100 mL of cold CH 2 Cl 2 was added, and the solution was separated once with 100 mL of saturated brine and three times with 100 mL of water. The organic layer was dried over anhydrous Na 2 SO 4 and evaporated. The crude product was separated by flash column chromatography (CH 2 Cl 2 : MeOH = 1: 0-4: 1) to obtain folate-linked porphyrin (ZnTFPP-triazole-TEG-FA) in a yield of 2.4%, Obtained with HPLC purity of 97%.
1 H NMR (600.17 MHz, acetone-d 6 , (CD 3 ) 2 CO = 2.05 ppm): δ (ppm) = 9.26-9.19 (9H, m, β-pyrroleH + pteridineC 7 H), 7.78-7.64 (5H , m, Ph-CONH + CH 2 CONHCH 2 + 2-PhH), 6.99-6.36 (3H, m, pteridineNH + pteridineC 6 -CH 2 NH-Ph + 3-PhH), 5.72 (2H, m, propargylCH 2 ) , 4.71-3.99 (4H, m, pteridineC 6 -CH 2 NH-Ph + NHCH), 3.65-3.32 (16H, m, NHCH 2 CH 2 O, CH 2 CH 2 O, OCH 2 , CH 2 CH 2 N 3 .), 2.37-0.83 (4H, m , CHCH 2 CH 2, CH 2 CONH) 19 F NMR (470.62 MHz, acetone-d 6, CF 3 CO 2 H = -76.50 ppm): δ (ppm) = -140.63 (2F, m, 3,5-PhF), -142.38 (2F, m, 2,6-PhF triazole-TEG-FA ), -157.16 (1F, m, 4-PhF), -158.68 (2F, m, 3,5-PhF triazole-TEG-FA ), -165.89 (2F, m, 2,6-PhF).
65Znポルフィリンの合成と体内動態評価
(1) PETサンプルの調製
使用サンプル濃度
TFPP(SGlc)trans-2： 2 mg/mL (1.5 mM)
Glu連結ポルフィリン TFPP(SGlc)trans-2を1.5 mMとなるようメタノール中に溶解し、溶解サンプル160μLに65Znを10 MBq 加えた。10分間のドライヤーによる加熱で錯体反応を起こし、その後エバポレータにより溶媒を除去した。得られた回収物に、PET造影剤の溶媒（EtOH:PEG 400:water = 2:3:5 (v:v:v)）を2.4 mLを加えて1.0μMの65Zn-TFPP(SGlc)trans-2を得た。
65 Synthesis and pharmacokinetics of Zn porphyrin
(1) Preparation of PET sample Concentration of sample used
TFPP (SGlc) trans-2: 2 mg / mL (1.5 mM)
Glu-linked porphyrin TFPP (SGlc) trans-2 was dissolved in methanol to a concentration of 1.5 mM, and 65 MB of 10 Znq was added to 160 μL of the dissolved sample. The complex reaction was caused by heating with a dryer for 10 minutes, and then the solvent was removed by an evaporator. Add 2.4 mL of PET contrast medium (EtOH: PEG 400: water = 2: 3: 5 (v: v: v)) to the collected material and add 1.0 μM 65 Zn-TFPP (SGlc) trans I got -2.
(2) 担癌マウスによる体内動態評価
担癌マウスは、BALB系ヌードマウスにRGK細胞を1×106cells (100μL)皮下移植して、1週間以上飼育することにより作成した。担癌マウスに対して上記要領で作成したPETサンプル血中投与後、1、3、24時間後にマウスを麻酔下で解剖し、臓器を摘出、摘出臓器のγカウンターによる放射線量の測定を行った。
摘出臓器：腫瘍、脳、心、肺、肝、腎、脾臓、血液
65Zn濃度：1×105 cpm/100μL
(2) Evaluation of pharmacokinetics using tumor-bearing mice Tumor-bearing mice were prepared by subcutaneously transplanting 1 × 10 6 cells (100 μL) of RGK cells into BALB nude mice and rearing them for 1 week or longer. After administration in the blood of PET samples prepared as described above for tumor-bearing mice, the mice were dissected under anesthesia 1, 3, and 24 hours later, the organs were removed, and the radiation dose was measured with a γ counter of the removed organs .
Isolated organs: tumor, brain, heart, lung, liver, kidney, spleen, blood
65 Zn concentration: 1 × 10 5 cpm / 100μL
(3) 実験結果
65Zn標識TFPP(SGlc)trans-2をマウスに尾静脈より血中投与した結果、TFPP(SGlc)trans-2は高いがん集積性を示した（図４：図中、左から1時間後、3時間後、24時間後のがん集積性を示す。）。TFPP(SGlc)trans-2は全臓器で高い値を示し、血液含有量が高い肝臓・腎臓・脾臓ではその傾向が顕著であった。血中の濃度をみるとTFPP(SGlc)trans-2は一定の値であり、経時的な変化は認められなかった（図５）。ここでマウスの体重を約20g、循環血液量1.7mLとして今回摘出した全臓器のTotal ID%を算出すると、24時間後にTFPP(SGlc)trans-2はTotal ID%≒73%（Blood ID%≒41.4）と投与したサンプルのほとんどが体内に残留していた（図６）。
(3) Experimental results
As a result of 65 Zn-labeled TFPP (SGlc) trans-2 being administered to mice via the tail vein, TFPP (SGlc) trans-2 showed high cancer accumulation (FIG. 4: 1 hour from the left in the figure) , Shows cancer accumulation after 3 hours and 24 hours.) TFPP (SGlc) trans-2 showed high values in all organs, and the tendency was remarkable in liver, kidney and spleen with high blood content. Looking at the blood concentration, TFPP (SGlc) trans-2 was a constant value, and no change over time was observed (FIG. 5). Calculating the total ID% of all the organs extracted this time, assuming that the weight of the mouse is about 20 g and the circulating blood volume is 1.7 mL. After 24 hours, TFPP (SGlc) trans-2 shows Total ID% ≒ 73% (Blood ID% ≒ 41.4) and most of the administered samples remained in the body (FIG. 6).
Claims (12)
R3、R6、R9及びR12は、それぞれ独立して、水素原子、任意に置換されてもよいC1-10アルキル、任意に置換されてもよいC2-10アルケニル、任意に置換されてもよいC2-10アルキニル、任意に置換されてもよいC6-14アリール、任意に置換されてもよいC7-20アリールアルキル、又は任意に置換されてもよい5〜14員ヘテロアリールを表し、ここで、置換基は、C1-6アルキル、C6-14アリール、C7-20アリールアルキル、OR20及びCOOR20（R20は前記と同様である。）、酸素原子、窒素原子、炭素原子又は硫黄原子が結合してもよい糖、ハロゲン原子、並びに次式：
で示される基からなる群から選ばれる少なくとも１つであり、
各置換基は、アミノ酸、葉酸、抗体、次式：
で示される基、アジ化物又はこれらの組み合わせを含む基でさらに置換されてもよく、
Mは、[64Cu]、[52Mn] 、[52Fe]、[99mTc]、[111In]、[68Ga]及び[62Zn]から選択される陽電子放出核種であり、
で示されるポルフィリン化合物を含む、腫瘍のPET診断用トレーサー。 Formula (I):
R 3 , R 6 , R 9 and R 12 are each independently a hydrogen atom, optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted Optionally substituted C 2-10 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-20 arylalkyl, or optionally substituted 5-14 membered hetero Represents aryl, wherein the substituents are C 1-6 alkyl, C 6-14 aryl, C 7-20 arylalkyl, OR 20 and COOR 20 (R 20 is as defined above), an oxygen atom, A sugar, halogen atom to which a nitrogen atom, carbon atom or sulfur atom may be bonded, as well as the following formula:
At least one selected from the group consisting of groups represented by:
Each substituent is an amino acid, folic acid, antibody,
May be further substituted with a group including a group represented by
M is a positron emitting nuclide selected from [ 64 Cu], [ 52 Mn], [ 52 Fe], [ 99m Tc], [ 111 In], [ 68 Ga] and [ 62 Zn],
A tracer for PET diagnosis of tumor, comprising a porphyrin compound represented by
で示される基からなる群から選ばれる少なくとも１つであり、
各置換基は、葉酸、次式：
で示される基、アジ化物又はこれらの組み合わせを含む基でさらに置換されてもよい、
請求項１または２に記載のトレーサー。 R 3 , R 6 , R 9 and R 12 each independently represent a hydrogen atom or an optionally substituted C 6-14 aryl, wherein the substituents are OR 20 and COOR 20 ( R 20 is the same as defined above), a sugar to which an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom may be bonded, a halogen atom, and the following formula:
At least one selected from the group consisting of groups represented by:
Each substituent is folic acid, the following formula:
Which may be further substituted with a group including
The tracer according to claim 1 or 2.
R3、R6、R9及びR12は、それぞれ独立して、任意に置換されてもよいC6-14アリールを表し、ここで、置換基は、酸素原子、窒素原子、炭素原子又は硫黄原子が結合してもよい糖、ハロゲン原子、並びに次式：
で示される基からなる群から選ばれる少なくとも１つである、請求項１〜３のいずれか１項に記載のトレーサー。 R 1 , R 2 , R 4 , R 5 , R 7 , R 8 , R 10 and R 11 represent a hydrogen atom,
R 3 , R 6 , R 9 and R 12 each independently represent optionally substituted C 6-14 aryl, wherein the substituent is an oxygen atom, nitrogen atom, carbon atom or sulfur A sugar to which an atom may be bonded, a halogen atom, and the following formula:
The tracer of any one of Claims 1-3 which is at least 1 chosen from the group which consists of group shown by these.
で示される基を表す。）で示される基である請求項１〜３のいずれか１項に記載のトレーサー。 A group having an amide bond is represented by —CONHCH 2 CH 2 NHCOCH 2 CH 2 COOR 40 (R 40 represents the following formula:
Represents a group represented by The tracer according to any one of claims 1 to 3, wherein the tracer is a group represented by
R3、R6、R9及びR12は、それぞれ独立して、水素原子、任意に置換されてもよいC1-10アルキル、任意に置換されてもよいC2-10アルケニル、任意に置換されてもよいC2-10アルキニル、任意に置換されてもよいC6-14アリール、任意に置換されてもよいC7-20アリールアルキル、又は任意に置換されてもよい5〜14員ヘテロアリールを表し、ここで、置換基は、C1-6アルキル、C6-14アリール、C7-20アリールアルキル、OR20及びCOOR20（R20は前記と同様である。）、酸素原子、窒素原子、炭素原子又は硫黄原子が結合してもよい糖、ハロゲン原子、並びに次式：
で示される基からなる群から選ばれる少なくとも１つであり、
各置換基は、アミノ酸、葉酸、抗体、次式：
で示される基、アジ化物又はこれらの組み合わせを含む基でさらに置換されてもよく、
で示されるポルフィリン化合物に、[64Cu]、[52Mn]、[52Fe]、[99mTc]、[111In]、[68Ga]及び[62Zn]から選択される陽電子放出核種を導入することを特徴とする、次式(I)：
で示される化合物の製造方法。 Formula (I '):
R 3 , R 6 , R 9 and R 12 are each independently a hydrogen atom, optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted Optionally substituted C 2-10 alkynyl, optionally substituted C 6-14 aryl, optionally substituted C 7-20 arylalkyl, or optionally substituted 5-14 membered hetero Represents aryl, wherein the substituents are C 1-6 alkyl, C 6-14 aryl, C 7-20 arylalkyl, OR 20 and COOR 20 (R 20 is as defined above), an oxygen atom, A sugar, halogen atom to which a nitrogen atom, carbon atom or sulfur atom may be bonded, as well as the following formula:
At least one selected from the group consisting of groups represented by:
Each substituent is an amino acid, folic acid, antibody,
May be further substituted with a group including a group represented by
A positron emitting nuclide selected from [ 64 Cu], [ 52 Mn], [ 52 Fe], [ 99m Tc], [ 111 In], [ 68 Ga] and [ 62 Zn] is introduced into the porphyrin compound represented by The following formula (I):
The manufacturing method of the compound shown by these.
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|---|---|---|---|---|
| JPH11130431A (en) * | 1997-10-30 | 1999-05-18 | Hamamatsu Photonics Kk | Gallium-68 chloride anhydride and gallium 68 complex of porphyrin derivative |
| US20030165426A1 (en) * | 2001-06-06 | 2003-09-04 | Michiko Miura | Use of novel metalloporphyrins as imageable tumor-targeting agents for radiation therapy |
| JP2010502574A (en) * | 2006-08-23 | 2010-01-28 | イエダ リサーチ アンド デベロップメント カンパニー リミテッド | Conjugate of RGD peptide and porphyrin or (bacterio) chlorophyll photosynthetic agent and use thereof |
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| JPH11130431A (en) * | 1997-10-30 | 1999-05-18 | Hamamatsu Photonics Kk | Gallium-68 chloride anhydride and gallium 68 complex of porphyrin derivative |
| US20030165426A1 (en) * | 2001-06-06 | 2003-09-04 | Michiko Miura | Use of novel metalloporphyrins as imageable tumor-targeting agents for radiation therapy |
| JP2010502574A (en) * | 2006-08-23 | 2010-01-28 | イエダ リサーチ アンド デベロップメント カンパニー リミテッド | Conjugate of RGD peptide and porphyrin or (bacterio) chlorophyll photosynthetic agent and use thereof |
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| FAZAELI, YOUSEF ET AL.: "Development of a 68Ga-Fluorinated Porphyrin Complex as a Possible PET Imaging Agent", NUCLEAR MEDICINE AND MOLECULAR IMAGING, vol. 46(1), JPN6017028837, 2012, pages 20 - 26, ISSN: 0003664053 * |
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