JPS62182663A - Radioactive metal-labelled cancer diagnostic agent - Google Patents

Abstract

PURPOSE:To reduce phototoxity by lowering the compatibility with healthy tissue, in a cancer diagnostic agent using a porphine derivative, by bonding a polyfunctional carboxylic acid to the side chain of the porphine compound. CONSTITUTION:Polyfunctional carboxylic acid is bonded to the side chain of a porphine compound having a porphine skeletal as shown by formula I (wherein R1 and R2 are -CHCH2, R3 is -H or -COOH, R4 is -H, A is -CH2-, the dotted line bonded to a gamma-position is a non-bond or a single bond, the dotted line between a 7-position and a 8-position is a single bond or a double bond and at least one of R1, R2, R3 and R4 is a group having R showing a polyfunctional carboxylic acid residue). The derivative thus obtained has the selective accumulation property to cancer tissue while has a characteristic rapidly excreted from normal tissue. When carboxylic acid provided with a group having a chelate forming capacity is used as the above mentioned carboxylic acid, the formation of a metal composite becomes easy. Therefore, when a radioactive metal is introduced as the metal, and derivative can be used as a radioactive metal- labelled diagnostic agent.

Description

DETAILED DESCRIPTION OF THE INVENTION (a) Field of Industrial Application The present invention relates to a radioactive metal-labeled cancer diagnostic agent, and particularly to a radioactive metal-labeled cancer diagnostic agent containing a novel metal complex of a porphyrin compound as an active ingredient.

In the present specification, the term "porphyrin derivative" is used in a broad sense, and is a general term for compounds having a basic skeleton represented by the following formula (hereinafter referred to as "porphine skeleton"). Two hydrogen atoms or protons attached to the nitrogen atom of the pyrrole ring are replaced by metal atoms or metal ions.1. The present invention provides metal complexes called fucroporphyrins, which are also encompassed by the term "porphyrin derivatives."

(b) Prior Art It has been well known that porphyrin derivatives have selective accumulation properties in cancer tissues.

However, while porphyrin derivatives exhibit toxicity when exposed to light, their selectivity towards cancerous tissues is not yet sufficient, so when they are administered to humans, patients are left with no choice until the porphyrin derivatives that have gathered in normal tissues are excreted from the body. Requires staying in the dark for long periods of time. As a result of various studies to overcome this defect, the present inventors have found that a metal complex of a porphyrin compound obtained by introducing a certain metal into the porphine skeleton maintains affinity for cancer. It was discovered that only the phototoxicity was reduced while the temperature remained unchanged (Japanese Patent Application Laid-open No. 83185/1985).

(c) Problems to be Solved by the Invention As mentioned above, the phototoxicity of porphyrin compounds can be reduced by introducing certain metals into the porphyrin skeleton, but the degree of reduction is not necessarily sufficient.

(d) Means to solve the problem As a result of further research in search of other methods to avoid the effects of phototoxicity, we found that by bonding a polyfunctional carboxylic acid to the side chain of a porphyrin compound, the porphyrin compound It has become clear that although the affinity for cancer is maintained, the affinity for healthy tissue is significantly reduced. In other words, derivatives of porphyrin compounds with polyfunctional carboxylic acids attached to their side chains have the property of selectively accumulating in cancer tissues, but are rapidly excreted from normal tissues, and are therefore susceptible to phototoxicity. There is no longer any need for special consideration. The properties of the above-mentioned porphyrin derivatives do not substantially change even if a metal is introduced into the porphine skeleton, and on the contrary, even more advantageous results can be obtained since the above-mentioned reduction in phototoxicity is observed.

Although it is not always easy to introduce a metal into the porphyrin skeleton depending on the type of metal, carboxylic acids with a group having chelate-forming ability (chelate-forming group) can be used as a polyfunctional carboxylic acid to be bonded to the side chain of a porphyrin compound. When used, the metal is captured by this chelate-forming group, making it easy to form a metal complex. Therefore, when a radioactive metal is introduced into a porphyrin compound for the purpose of using it as a radioactive metal-labeled diagnostic agent, the introduction is easy, but there is also the advantage that the amount introduced per molecule is large.

The present invention was completed based on the above findings, and the gist thereof is as follows: Formula: (wherein R1 and R2 are respectively -CH-CR2, -
CI-1, CI-T, -CH(0-lower alkanoyl)CHs, -CI((OR)CR3 or -CH(0-
lower alkylene-OR) CI-I 3, R3 is -1-
1,-COOHl-C0〇-lower alkyl, -COO-
Lower alkylene-OR or -C00-lower alkylene-00C-Z, R, is -■4, -lower alkyl or -
Lower alkylene -OR, R is =I], -lower alkyl or a residue obtained by removing hydrogen from a polyfunctional carboxylic acid, Z is a residue obtained by removing R3 from the compound of formula (1), A is -CH2-
Or, the dotted line bonded to the -C0-1γ position indicates no bond or a single bond, and the dotted line between the 7th and 8th positions indicates the presence of a single bond or a double bond. However, at least one of R1, R1, R8 and R4 must be a group having R representing a polyfunctional carboxylic acid residue. ) A metal complex of a porphine compound represented by (needs to be a radioactive metal) as an active ingredient.

The term "lower alkylene" used in connection with the meanings of the above symbols means alkylene having 5 or less carbon atoms, preferably 1 to 3 carbon atoms (eg, ethylene, trimethylene, propylene). Further, the term "lower alkyl" means an alkyl having 8 or less carbon atoms, preferably 1 to 3 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl). Furthermore, the term "lower alkanoyl" means an alkanoyl having 8 or less carbon atoms, preferably 3 or less carbon atoms (eg, acetyl, propionyl).

The term "polyfunctional carboxylic acid" refers to one carboxyl group plus at least one functional group (e.g. -NHZ,
-OH, -SH, -COOH). Preferably, physiologically acceptable amino acids are used, such as glycine, cysteine, glutamic acid, alanine, cystine, asparagine, valine, methionine, glutamine, leucine, phenylalanine, isoleucine, serine, tryptophan, threonine, aspartic acid, etc. It's okay to be. Further, it is more preferable to use a physiologically acceptable substance having a chelate-forming functional group, and specific examples thereof include ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (D
TPA), 1,2-bis(0-aminophenoxy)
Ethane-N,N,N',N'-tetraacetic acid (B A P
T A), 1,3-diaminopropan-2-ol-
N,N,N',N'-tetraacetic acid (DPTA-OH)
, trans-1,2-cyclohexanediamine-N,N
, N', N'-tetraacetic acid (CYD TA) 1, N-
Hydroxyethylethylenediamine-N, N', N'-
) diacetic acid (EDTA-OH), ethylenediamine-N,
N'-diacetic acid (EDDA), iminodiacetic acid (IDA),
Ethylenediamine-di(0-hydroxyphenylacetic acid
EDDHA), etc. Note that these may be used in the form of alkali metal salts.

The porphyrin compound represented by formula (I) includes at least two types of compound groups. Specifically, one of them is a group of compounds in which A is -CHt in formula (1), a dotted line bonded to the γ position indicates no bond, and a dotted line between the 7th and 8th positions indicates the presence of a double bond (porphins). ), and the others are formulas (
In I), the dotted line in which A is bonded to the -co-1γ position indicates the presence of a single bond, and the dotted line in the 7th and 8th positions indicates the presence of a single bond (polvins).

When the polyfunctional carboxylic acid residue has a chelate-forming group, the metal complex of the porphyrin compound (H) includes at least three types of complexes.

In other words, metal is bonded only to the porphine skeleton,
There are three types: one in which the metal is bonded only to the polyfunctional carboxylic acid residue, and one in which the metal is bonded to both the porphine skeleton and the polyfunctional carboxylic acid residue.

Porphyrin compounds used as active ingredients in the present invention (
The metal composite I) is a new substance and can be produced by a conventional method.

Usually, first, a porphyrin compound corresponding to formula (1) having R in which at least one of R+-Rz, R3 and R4 is hydrogen is constituted and step (a)),
Next, a step of introducing a polyfunctional carboxylic acid residue (
b)), prepared by bonding the metal before or/and after this introduction step (b) (step (C)).

The composition step (a) is described in "Chemistry of Porphyrins" by Naga et al. (Kyoritsu Shuppan Publishing, 1982) and "Porphyrins and Metalloporphyrins" (P. Falk).

Rphyrins and Metalloporph
Dolphin, The Porphyrins (1975)
This can be done by conventional methods such as those described in The Porphyrins (Academic Press, 1978). For example, porphyrin compounds corresponding to the formula (D in which R is hydrogen) are disclosed in JP-A-61-7279 and JP-A-61-8318.
This may be prepared according to the method described in Publication No. 5. Instead of artificially synthesizing it, it can also be obtained from natural sources such as plants and animals.

The porphyrin compound thus constructed is then subjected to the step (b) of introducing a polyfunctional carboxylic acid residue. That is, a polyfunctional carboxylic acid or a reactive derivative thereof is reacted with a porphyrin compound (1) having R in which at least one of RISR2, R3, and R4 is hydrogen, and a polyfunctional carboxylic acid or a reactive derivative thereof is reacted to form R8, R3, R3, and R4. A porphyrin compound (I) in which at least one R does not represent a polyfunctional carboxylic acid residue is produced. In this case, the point is to introduce a residue of a polyfunctional carboxylic acid into the side chain of the porphyrin compound (1), so the polyfunctional carboxylic acid may be reacted with its carboxyl group, and other functionalities may be reacted. The reaction may be carried out on groups.

For example, when using an amino acid as a polyfunctional carboxylic acid, it is generally preferable to allow the reaction to proceed between the carboxyl group present in the side chain of the porphyrin compound (1) and the amino group of the amino acid. The carboxyl group of a carboxylic acid having a carboxyl group and a chelate-forming group and/or the amino group of the latter can be converted into a conventional reactive group, or the functional group present in both that is undesirable to participate in the reaction can be appropriately converted. Protection may be considered. In addition, when using a carboxylic acid having a chelate-forming group as the polyfunctional carboxylic acid, the hydroxyl group present in the side chain of the porphyrin compound (I) and the carboxyl group of the carboxylic acid having a chelate-forming group may It is preferable to allow the reaction to proceed between the two, and for this purpose, conversion of the hydroxyl group and/or carboxyl group to a reactive group or protection of the functional group may be considered as described above.

In any case, use of a reaction accelerator or condensing agent such as a dehydrating agent or deoxidizing agent may be considered as appropriate.

A metal bonding step (c) is performed before and/or after the introduction step (b). Porphine skeleton or/
and the binding of metals in polyfunctional carboxylic acid residues.
This is usually done using metal halides, sulfates, nitrates, etc. The types of metals are S1. Mn
, F 8% Co, N lq Zn1Ga, In,
There are Sn, Sm, Eu, GcL Tc5Ti, etc. Depending on the type of metal, there may be some differences in the location and difficulty of bonding. It is particularly preferable to use radioactive metals for the diagnosis or treatment of cancer.
Examples include a, ■'I nS'''TQ, and ``mTc. On the other hand, preferred non-radioactive metals include Si and Go.
, Ni, ZnSGa, In.

Examples include Sn.

Hereinafter, the preparation of the porphyrin compound (I) and its metal composite will be explained in more detail using representative examples.

For example, when the polyfunctional carboxylic acid residue is a residue of DTPA (diethylenetriaminepentaacetic acid), first, a porphyrin compound or A metal complex in which a metal is bound to the porphine skeleton (JP-A-61-7279 or JP-A-61-83185) is reacted with DTPA under heating in pyridine to form a DTPA residue in the side chain. The bound porphyrin compound (
I) and a metal composite in which a metal is bonded to the porphine skeleton. Specific examples include the following: (1) Ethylene glycol Mono-diethylenetriamine-4-acetic acid-acetate Mono-10b-methylpheophorbate (hereinafter referred to as DTPA-10EG P
PB-Me) (2) 2-desethynyl-2-[1-(diethylenetriamine-4acetic acid-acetyloxyethane)okynethyl]medilfeo71;-bite (hereinafter referred to as DTPA-2EG)
(referred to as PPB-Me) (3) Ethylene glycol mono-diethylenetriamine-4-acetic acid-acetate mono-7cm pyropheophorate (hereinafter referred to as DTPA-7EG pyroP P B
(4) Ethylene glycol Mono-diethylenetriamine-4-acetic acid-acetate Mono-70-pheophorbate (hereinafter referred to as DTPA-7EG PPB) (5) Ethylene glycol Mono-diethylenetriamine-4-acetic acid-acetate Mono-10b-pheophorate Hobate (hereinafter referred to as DTPA-10EG PPB) (6) 2-[1-(diethylenetriamine-4-acetic acid-
acetyloxyethane)oxyethyl]-4-[1-(
2-hydroxyethyloxy)ethylcomethyl deuteroporphyrin (hereinafter referred to as DTPA-EGDP-Me) (7) 2-[1-(diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4-[+-(2
-Hydroxyethyloxy)edyl] deuteroporphyrin (hereinafter monoD T P A -E G D
(8) 2,4-bis[1-(diethylenetriamine-4
acetic acid-acetyloxyethane)oxyethyl] deuteroporphyrin (hereinafter referred to as bisDTPA-EGDP) (9) 2-[1-(diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4-[1-(2
-Hydroxyethyloxy)ethyl]Ga-deuteroporphyrin (hereinafter monoD T P A -E G
(referred to as Ga-DP) (10) 2.4-bis[l-(diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]Ga
-1 niteroporphyrin (hereinafter bisDTPA-EG
(11) 2-[1-(diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4-[1-
(2-hydroxyethyloxy)ethyl]In-deuteroporphyrin (hereinafter monoDTPA-E
(referred to as GIn-DP) (12) 2.4-bis[1-(diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]In
- deuteroporphyrin (hereinafter bisDTPA-EG
In-DP) etc.

The thus prepared porphyrin compounds and the metal complexes in their porphine skeletons were treated with metal chlorides (e.g., InCl, SmC, etc.) in a chloroform-methanol mixture.
(b, When reacted with EuC (2a, G d C123), the metal is captured by the DTPA residue, resulting in a metal complex of a porphyrin compound in which the metal is bound to the corresponding DTPA residue. Specific examples thereof include: The following can be mentioned: (13) Ethylene glycol In-mono-diethylenetriamine-4-acetic acid-acetate Mono-1Ob-methylpheophorbate (hereinafter In-DTPA-10EG
(referred to as PPB-Me) (14) Ethylene glycol
In-mono-diethylenetriamine-4-acetic acid-acetate mono-7C-pyropheophorate (hereinafter referred to as In-D
TPA-7EG pyroPPB) (15) 2-[1-(I n-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4
-[1-(2-hydroxyethyloxy)ethyl] deuteroporphyrin dimethyl ester (hereinafter In-D
TPA-EG DP-Me) (16) 2-[
1-(In-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4-[1-(2-hydroxyethyloxy)edyl]deuteroporphyrin (hereinafter referred to as In-monoD TPA-EGD
(17) 2.4-bis[1-(In-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]deuteroporphyrin (hereinafter referred to as In-bisDTPA)
-EG DP) (18) 2-[1-(Sm-diethylenetriamine-
4-acetic acid-acetyloxyethane)oxyethyl]-4-
[1-(2-hydroxyethyloxy)ethyl] deuteroporphyrin (hereinafter referred to as Sm-DTPA-EG DP
(19) 2-[1-(Eu-diethylenetriamine-
4-acetic acid-acetyloxyethane)oxyethyl]-4-
[+-(2-hydroxyethyloxy)ethyl] deuteroporphyrin (hereinafter referred to as Eu-DTPA-EG DP)
(20) 2-[1-(Gd-diethylenetriamine-
4-acetic acid-acetyloxyethane)oxyethyl]-4-
[+-(2-hydroxyethyloxy)ethylcodeuteroborphyrin dimethyl ester (hereinafter referred to as Gd-DT
PA-EG DP-Me) (21) 2-[+
-(Gd-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4-[1-(2-hydroxyethyloxy)edylcodeuteroborphyrin (
(hereinafter referred to as Gd-DTPA-EG DP) (22) 2-[1-(I n-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl] ~ 4
-[1-(2-hydroxyethyloxy)ethylcoGa
- Deuteroporphyrin (hereinafter In-monoDTP)
A-EG Ga-DP) (23) 2.4-bis[1-(In-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]Ga-deuteroporphyrin (hereinafter referred to as Ir+ -bi
(24) 2-[1-(In-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]
-4-[1-(2-hydroxyethyloxy)ethyl]
In-deuteroporphyrin (hereinafter referred to as In-monoD)
TPA-EG In-DP) (25) 2.4-bis[1-(In-diethylenetriamine-4acetic acid-acetyloxyethane)oxyedyl]In-deuteroporphyrin (hereinafter referred to as In-bisD)
It is called TPA-EG In-DP (26) 2-[+
-(Gb-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4-[1-(2-hydroxyethyloxy)ethyl]Gd-deuteroporphyrin (hereinafter Gd-monoDTPA-EG Ga-D
(27) 2.4-bis[1-(Gd-diethylenetriamine-4acetic acid-acetyloxyethane)oxyedyl]Ga-deuteroporphyrin (hereinafter referred to as “Gd-bis
DTPA-EG Ga-DP) (2g) 2-
[1-(Ga diethylenetriamine-4acetic acid-acetyloxyethane)-4-(1-hydroxyethyloxyethyl)oxyethyl]Ga-deuteroporphyrin (hereinafter referred to as Ga-monoD T P A-EG G
a-DP) (29) 2.4-bis[1-(Ga-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]Ga-deuteroporphyrin (hereinafter referred to as Ga-bisD)
TPA-EG Ga-DP) etc.

In addition, when the polyfunctional group is a residue of glycine or glutamic acid, first, a porphyrin compound in which at least one of R1, R1, R3, and R4 is a group having R representing hydrogen or a metal in its porphine skeleton is used. Bonded metal composite (JP-A No. 61-7279 or No. 61
-83185) in the presence of a condensing agent (e.g. dicyclohexylcarbodiimide (DDC)) and an inert solvent (
For example, glycine or glutamic acid is reacted in chloroform). In this case, the raw material porphyrin compound is preferably reacted in the form of dicyclohexylamine or (DCHA) salt, and the glycine and glutamic acid are preferably reacted in the form of lower alkyl ester (for example, methyl ester).

In this way, a porphyrin compound (1) is obtained, specific examples of which include: (30) hemadoporphinyl diglycine (hereinafter referred to as HP-gly) (31) hemadoporphinyl diglutamic acid (hereinafter referred to as H
P-glu) (32) Diacetylhemadoporphinyl diglycine (
(hereinafter referred to as HDA-gly) (33) diacetylhemadoporphinyl diglutamic acid (hereinafter referred to as HDA-glu), etc.

These porphyrin compounds (I) are heated with a metal chloride (for example, InCl2+) in acetic acid to give a metal complex in which a metal is bonded to a porphine skeleton. Examples of such metal complexes are as follows: (34) In-hematoporphinyl diglycine (hereinafter referred to as In-HP-gly) (35) In-hematoporphinyl diglycine (hereinafter referred to as In-HP-gly)
(hereinafter referred to as In-HP-glu) (36) In-diacetylhemadoporphinyl diglydine (hereinafter referred to as In-HDA gl)') (37)
In-diacetylhemadoporphinyl diglutamic acid (hereinafter referred to as In-HDA-glu), and the like.

Porphyrin compounds in which the bound metal is a radioactive metal (1)
The metal complex can be prepared from the corresponding porphyrin compound (I) and the corresponding radioactive metal compound in the same manner as described above. For example, radioactive metal @7Ga
, "1■n or !OI T (t, respectively"GaCQs,"'InC12a or !07T
QCQ3 may be used. In addition, radioactive metals are “mT”
c, pertechnetate (e.g. Na”
mTco+) in conjunction with a suitable reducing agent (eg, sodium hydrosulfide, stannous chloride). A specific example of the metal complex of the porphyrin compound (H) thus obtained is as follows: (3g) ■'In-hemadoporphinyl diglycine (
(hereinafter referred to as 口'I n -HP-gly) (39)"
'In-hemadoporphinyl diglutamic acid (hereinafter "
'I n-HP-glu) (40) ``'
I n-diacetyl hematoporfinyl diglycine (hereinafter referred to as A-glu) (41) “Ga-hematoporfinyl diglycine (
(hereinafter referred to as “Ga-HP-gly”) (42) “Ga
-Hemadoporphinyl diglutamic acid (hereinafter “Ga
-HP-glu) (43) “Ga-diacetyl hematoporphinyl diglutamic acid (hereinafter referred to as “Ga-HD”)
A-glu) (44) ``TI-hematoporphinyl diglycine (hereinafter referred to as ``Tl-HP-gly'') (45) ``'TI-hematoporphinyl diglutamic acid (hereinafter referred to as ``TI-HP-glu'') say) (46
) t0'Tl-diacetylhematoborfinyldiglutamic acid (hereinafter referred to as "T I-HD A-glu (4
7) Ethylene glycol l l l I n-mono-
Diethylenetriamine-4 acetic acid-acetate mono-1
0b-methylpheophorbate (hereinafter + 111 n
-DTPA-10EG PpB-Me) (48
) 2 [1-(''I n-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-
4-[1-(2-hydroxyethyloxy)ethyl] deuteroporphyrin dimethyl ester (hereinafter referred to as "'I")
n-DTPA-EG DP-Me) (49)2 [1-("'In-diethylenetriamine-tetraacetic acid-acetyloxyethane)oxyethyl]-
4-[1-(2-hydroxyethyloxy)ethyl] deuteroporphyrin (hereinafter referred to as ``In-mon'').

D'l'PA-EG DP) (50) 2,4-bis[1-(''I n-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl] deuteroporphyrin (hereinafter referred to as + 11 In
-bisDTPA-EG DP) (51) 2
-[1-(''' In-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4-[1-
(2-hydroxyethyloxy)ethyl]Ga-deuteroporphyrin (hereinafter referred to as 1 In-monoDTPA-
EG Ga-DP) (52) 2.4-bis[
1-(”' I n-diethylenetriamine-4 acetic acid-
acetyloxyethane)oxyethyl]Ga-deuteroporphyrin (hereinafter "'In-bisDTPA-EG"
(referred to as Ga-DP) (53) Ethylene glycol
"Ga-mono-diethylenetriamine-4-acetic acid-acetate mono-tob-methylpheophorbate (hereinafter")
Ga-DTPA-10EG PPB-Me) (
54) 2-[1-(”Ga-diethylenetriamine-
4-acetic acid-acetyloxyethane)oxyethyl]-4-
[1-(2-hydroxyethyloxy)ethyl] deuteroporphyrin dimethyl ester (hereinafter referred to as “Ga-D”)
TPA-EG DP-Me) (55) 2-[
1-("Ga-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl 1-4-[1-(2-hydroxyethyloxy)ethyl] deuteroporphyrin (hereinafter referred to as "Ga-monoDTPA-EG DP") (56) 2.4-bis[1-("Ga-diethylenetriamine-4acetic acid-acetyloxyethane)okinoedyl] deuteroporphyrin (hereinafter "Ga-bisDTP")
A-EG DP) (57) 2-[1-(“Ga-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4
-[+-(2-hydroxyethyloxy)ethyl]Ga
- Deuteroporphyrin (hereinafter referred to as "Gamon").

DTPA-EG Ga-DP) (5g) 2.
4-bis[1-("Ga-diethylenetriamine-4acetyloxyethane)oxyethyl]Ga-deuteroporphyrin (hereinafter "Ga-bisDTPA-E")
C; called Ga-DP) (59) Ethylene glycol
Acetate mono-10b-methylpheophorbate (
Below 101T, 2-DTPA-10EG PPB-M
e) (60) 2- [1-("'l!l diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4-[1-(2-hydroxyethyloxy)ethylcodeuteroborphyrin Dimethyl ester (hereinafter referred to as 20'TQ-DTPA-EG DP-Me) (61) 2-[1-("'T12-diethylenetriamine-tetraacetic acid~acetyloxyethane)oxyethyl]
-4-[1-(2-hydroxyethyloxy)edyl]
Deuteroporphyrin (hereinafter referred to as "'TQ-mon").

DTPA-EG DP) (62) 2.4-bis[1-(''T+2-diethylenetriamine-tetraacetic acid-acetyloxyethane)oxyethyl]deuteroporphyrin (hereinafter = 01 Tc
-bisDTPA-EG DP) (63) 2
-[1-(”'Tρ-diethylenetriamine-tetraacetic acid-
acetyloxy, siethane)oxyethyl]-4-[1-
(2-hydroxyethyloxy)ethyl]Ga-deuteroporphyrin (hereinafter referred to as 201 T Q-monoDT
PA-EG Ga-DP) (64) 2.4-
Bis[1-(''T12-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]Ga-deuteroporphyrin (hereinafter 2G+TQ-bisDTPA
-ECGa-DP) (65) Ethylene glycol 99mTc-mono-diethylenetriamine-4-acetic acid-acetate Mono-job-methylpheophorbate (hereinafter referred to as "mTc-I") TPA-l OEG PPB-Me
(66) 2-[1-("mTc-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4-[1-(2-hydroxyethyloxy)edyl] deuteroporphyrin dimethyl ester (hereinafter referred to as 89mTc- DTPA-EG DP-Me) (67) 2 [1-(l19mTc-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-4-[1=(2-hydroxyethyloxy)ethyl] deuteroporphyrin (hereinafter referred to as DP-Me) 99mT c-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl] deuteroporphyrin (hereinafter referred to as "mTc-
biaDTPA-EG Dr) (68) 2
．． 4-bis["mTc-diethylenetriamine-4acetic acid-acetyloxyethane]oxyethylcodeuteroborphyrin (hereinafter "mTc-bisDTPA-EG D
(69) 2-[1-(“mTc-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]-
4-[1-(2-hydroxyethyloxy)ethyl]G
a-deuteroporphyrin (hereinafter 911InTC-m)
onoDTPA-EG Ga-DP) (70)
2.4-bis[1(”m Tc-diethylenetriamine-4acetic acid-acetyloxyethane)oxyethyl]Ga
- deuteroporphyrin (hereinafter 99+++Tc-bi
sDTPA-EG Ga-DP), etc.

(E) Effect The porphyrin compound (I) and its metal complex according to the present invention have a chemical structural feature in that they have a polyfunctional carboxylic acid residue in the side chain of the porphine skeleton, and as a result, the exhibit physiological or pharmacological properties. That is, these porphyrin derivatives selectively accumulate in cancer cells and are slowly excreted from cancer cells. In particular, metal complexes do not react when exposed to light, but when exposed to external energy other than light, such as microwaves or electromagnetic waves, they react and become excited, producing singlet oxygen with strong oxidizing properties, which can kill cancer cells. Destroy. Note that it is quickly excreted from normal organs and cells, so it does not cause any damage to them.

Originally, most porphyrin derivatives have a strong effect on light, but according to the present invention, polyfunctional carboxylic acid residues are introduced into their side chains, and if necessary, these are converted into metal complexes. By doing so, excretion from normal tissues was increased and phototoxicity was reduced, making it possible to suppress the expression of phototoxicity while maintaining selective concentration on cancer cells.

As described above, the porphyrin derivative of the present invention can react to external energy without substantially exhibiting phototoxicity, and moreover, when a chelate-forming group is present in the polyfunctional carboxylic acid residue, it can react with metals. can be universally and easily combined.

Based on these properties (cancer affinity, non-phototoxicity, cancer destruction by external energy, ability to form metal complexes, etc.), the porphyrin derivatives of the present invention are particularly useful as diagnostic agents, markers, missile therapy agents, etc. for cancer and malignant tumors. Useful.

(f) Examples The pharmacological effects and manufacturing method of the substance of the present application will be explained below using examples.

Example 1 Laser irradiation at the excised organ (excitation fluorescence spectrum) Colden hamsters (group of 5 animals) aged 14 to 21 days after transplantation of nitrosamine carcinogenic pancreatic cancer cells were diluted with 0.1 M citrate buffer (1 yen) 5x9 test drug DT
After intravenous injection of PA-I QEG PPB-Me,
Cancer cells and other organs are removed, and each organ is treated with Nx-pulsed 1aser (N*).

337Gm, 2ns400=1000Gm),
The excitation fluorescence spectrum was measured, and wavelengths from 600 to 900 Gm were examined based on the NADH peak wavelength of 470 Gm.

Table 1 shows the results obtained by performing the same operation below.

Table 1 Compound\Organ Cancer Liver Lung Kidney Serum (1) DTPA-10EGPPB-Me 2
．． 73 0.69 0.47 0!7 0.53(2)
DTPA-2EGPPB-Me 1.32
0.93 1,00 0.31 0.42 (3) DTP
A-7EGpyroPPB 2.2'OO, 8
71,230,250,39(4)DTPA-7EGP
PB O, 530, 330, 300, 32
0,31(5)DTPA-10EGPP[l,
1,20 0.77 0.45 G, 43
0.52(6)DTPA-EGDPMe
O,760,090,0g 0.0B 0.32(
9) monoDTPA-EGGa-DP O,
830,190,06G,33 1.21(10)bi
sDTPA-EGGa-DP O,860,1
50,06(1,100,34(11)monoDTr
'A-EGIn-DP [1,390,030
,150,000,16(+2)bisDTPA-EG
In-DP 0.47 0.12 0.13
G, 13 0.18 (13) In-DTPA-10E
GPPB-Me 1.03 0.43 0.19
0.12 0.34(14)In-DTPA-7EG
'pyroPf'B 1.25 Q, 52 0
．． 47 0.42 0.45(15)In-DTPA-
EGDP-Me O,83G,36 0.09
G, 15 0.71Continued from Table 1Compound\Organ Cancer Liver Lung Kidney Serum (1g) Ss-DTPA-EGDP 1
．． 0? fl, 10 0.12 0.11 0.85
(19) Eu-DTPA-EGDP 1.
33 0. Q9 0.14 0.03 0.43 (20
) Gd-DTPA-EGDP-Me O,60
0,120,07G,05/(21)Gd-DT
PA-EGDP 2.10 +1.26
0.14 0.03 1.0G (22) In-mon
oDTPA-EGGa-DP 0.50 0.03
G, 14 0.05 G, 02 (23) In-b
isDTPA-EGGa-DPO,400,18/
0.10 0.03 (24) In-ShizuonoDTPA
-EGIn-DP O,300,07G,09
G, 80 0.24(25) In-bisDTPA-E
GIn-DP 'Q, GOO, 250,050,0
50,05(3G)IIP-gly'
1.94 0.39 0.35 0.32 3.
51 (31) [IP-glu 1
．． 79 0.45 0.37 0.33 5.43 (3
2) HDA-gly 2.20
0.33 0.86 G, 39 5.62 (33) I
IDA-glu 2.69 0.3
3 1.09 0.36 5.12 (34) In-11
P-gly' 0.29 0.01
G, 03'0.0g 0.32(35)In
-IP-glu O,400,210
,100,060,90(:(6)In-HDA-gl
y 1.2G 0.16 0.50
G, 36 4.06 (37) In-11D^-gl
u 2.90 0.35 0.33 0
．． 20 7.39 Table 1 shows the excitation fluorescence spectra of each organ excised 24 hours later, measured at a NA of 470 Gm.
600-900nr based on the peak wavelength of DH
The calculated value of the peak wavelength in II is shown.

As is clear from the results in Table 1, these porphyrin-related compounds have a remarkable selective affinity for cancer cells.

Example 2 Ethylene glycol mono-10b-methylpheophorbate tg was dissolved in pyridine 50x12 and DTPAl
, 59 was added, and the mixture was allowed to react for 3 hours under heating and stirring. The end point of the reaction is confirmed by TLC [MeOH-IOAC (5:2)] as a product around Rf=0.6. After the reaction, excess DTPA is filtered off and ethyl acetate is added to the filtrate to precipitate crystals.

This was subjected to silicic acid column chromatography (ethyl acetate-methanol), and DTPA-10EGPPB-Meo
, 59 were obtained. (Yield 31.4%) Example 3 1 g of 2-desethynyl-2-(1-ethanealcoholoxyethyl)methylpheophobite was added to Collidine 50M
The mixture was dissolved in Q and DTPAlg was added, followed by reaction at 50° C. for 2 hours under reduced pressure. The following operation was performed in the same manner as in Example 2, and the DTP
2g of A-2EG PPB-Meo was obtained. (Yield 12
．． 5%) Example 4 1 g of ethylene glycol mono-7C-pyropheophorate was dissolved in 60 mQ of picoline and DTPAI! ? was added and left to react at room temperature for one week. The following operation was performed in the same manner as in Example 2, and DTPA-7E G pyroP
PBO, 19 was obtained. (Yield 6.1%) Example 5 Ethylene glycol mono-70-pheophorbate 1
Dissolve g in DMF50 sake and add DTPAI.

5 g of silica gel I9 was added, and the mixture was allowed to react under heating and stirring. The following operation was carried out in the same manner as in Example 2, and DTPA-7EG
PPBO O,ty was obtained. (Yield 6°3%) Example 6 Ethylene glycol mono-10b-pheophorbate 19 was dissolved in pyridine 50RQ, DTPAl, 5g,
Add 1 g of zeolite and react under heating and stirring. The following operation was performed in the same manner as in Example 2, and DTPA-10EG P
4 g of PBO was obtained. (Yield 25%) Example 7 1 g of 2.4bis[1-(2-hydroxyethyloxy)ethylcomethyl deuteroporphyrin was added to 50% of picoline.
Dissolve in xQ, add DTPAl9, and react under heating and stirring. The following operation was carried out in the same manner as in Example 2, and DTPA-E
GDP-Meo, 69 was obtained.

(Yield 37.7%) Example 8 2.4bis[1-(2-hydroxyethyloxy)edyl]deuteroporphyrin Ig was dissolved in 70 mQ of pyridine, and DTPA I! ? Add and react under heating and stirring. The end point of the reaction is TLC[MeOH-HOA
c(5:2)], two products with Rr=o, around 6 and Rf= around 0°3 were confirmed, and the following operation was carried out in the same manner as in Example 2.

These two components were subjected to silicic acid column chromatography (ethyl acetate-methanol) and monoDTPA
-E G D P O, 49 and bisDTPA-
EG DP O,49 were obtained, respectively. (Yield 25
．． 8% and 19.1%) Example 9 1 g of 2.4bis[1-(2-hydroxyethyloxy)ethyl]Ga-deuteroporphyrin was dissolved in 70% pyridine.
Dissolve the mixture in liqueur, add DTPAlg, and react under heating and reduced pressure. The following operations were performed in the same manner as in Example 8, and the monoDTP
A-EG Ga-DP 0.39 and bisDTPA
-EG Ga-DP 0.39 was obtained, respectively. (
Yields 20.3% and 15.4%) Example 10 2.4bis[1-(2-hydroxyethyloxy).

Ethyl] In-deuteroporphyrin 17 was dissolved in collidine 70tQ, DTPAtg was added, and the mixture was allowed to react under heating and stirring. The following operations were carried out in the same manner as in Example 8, and the mo
noDTPA-EG' In-DP 0.52 and b
isDTPA-EG In-DP 0.49 was obtained respectively. (Yields 35.5% and 22.0%) Example 2 The respective compounds obtained in Example 2.4.7.8.9.10, namely DTPA I OEG PPB -Me.

DTPA-7EG pyroPPB.

DTPA-EG DP-Me.

monoDT　P　A　-E　G　D　P.

bis-DTPA-EG DP.

monoDTPA-EG Ga-DP%bisDT
PA-EG Ga-DP.

monoDTPA-EG I n-DP and bis
Each 19 of DTPA-EG In-DP was separately dissolved in 100 mQ of CT-(Cl3-MeOH (3:1), and a calculated amount of InCIa dissolved in 2 tQ of water was added to this.
When added, a complex is immediately formed. (Changes in color tone were confirmed by TLC, visual inspection, and ultraviolet hand scope). The resulting complexes were concentrated to dryness under reduced pressure to yield In-DTPA-10EG PPG-Me, respectively.

In-DTPA-7EG pyroPPB.

In-DTPA-EG DP-Me.

In-monoDTPA-EG DP.

In-bisDTPA-EG DP.

In-monoDTPA-EG Ga-DP.

In-bisDTPA-EG Ga-DP.

In-monoDTPA-EG In-DP and In-bisDTPA-EG In-DP were each obtained in 100% yield.

Example 12 DTP obtained in Example 8
[mon.

:bis(3:1) mixture 1g to CHC13M
Dissolved in 100 m of eOH (4:1), add 21 m of water to this
The calculated amounts of 5IIIC13, EuC1a and G d Cl s dissolved in 1Q are added separately to immediately form a complex. Thereafter, the same procedure as in Example 11 was performed to obtain Sm-DTPA-EG DP.

Eu-DTPA-EG DP and Gd-DTPA-EG DP were each obtained in 100% yield.

Example 13 monoDTPA-EG obtained in Example 9
Ga-DP and bisDTPA-EG Ga
- Each of the DPs! 9 to CHCl3 MeOI-I (1:1)
20011Q and to which a calculated amount of Gd-Cl3 dissolved in water 2Wσ is added separately to immediately form a complex.

The following operations were carried out in the same manner as in Example 11 to obtain Gd-monoDTPA-BG Ga-DP and Gd-bisDTPA-EC; Ga-DP with a yield of 100%.

Example 14 monoDTPA-EG obtained in Example 9
G a-DP and bisD'rPA-EG G
Each 19 of a-DP was dissolved in CHCl3MeOH (1:1)
When a calculated amount of Gacl* dissolved in 2 mQ of pyridine is added separately to this, a complex is immediately formed.The following operation is carried out in the same manner as in Example 11,
Ga-monoDTPA-EG Ga-DP and Ga-bisDTPA-EG Ga-DP were each obtained with a yield of 100%.

Example 15 1 g of hematoporphyrin was dissolved in THF30xQ, and D CHA 2yt (
Add l to react. Crystals precipitate when ether is added to the reaction solution. Collect these crystals and use D in ether.
CI-IA was filtered off to obtain 1.49 ml of hematoporphyrin DCHA salt. (Yield 90.0%) Example 16 1 g of diacetyl hemadoporphyrin was operated in the same manner as in Example 15 to obtain 1.49 CHA salt of diacetyl hemadoporphyrin D. (Yield 94.6%) Example 17 350 ml of CHCl was added to 1 g of the hematoporphyrin DCHA salt obtained in Example 15, and then 0.6 g of glycine ethyl hydrochloride was added, and while stirring, DCCo, 5
g was added dropwise and allowed to react for 2 hours. - After leaving it overnight (T L
Confirmed with C [toluene-acetone (1:1)]), concentrated under reduced pressure, and added ethyl acetate to the residue.
Filter off the CU rea. After concentrating the filtrate under reduced pressure, HP-gl
y-ethyl ester was obtained. Add this to 50mQ of alcohol.
Add and dissolve, and add N/2KOH alcohol until the hydrolysis reaction is completed. After the reaction, add water and add a trace amount of DCUr.
Filter off the ea again. When the filtrate was made acidic (PI(4)) by adding 10% citric acid, crystals precipitated. The crystals were collected by filtration, washed with water, and dried to obtain 8 g of HP-glio.

(Yield 71°4%) Example 18 Hematoporphyrin DCHA salt 1 obtained in Example 15
To 9, CHCl and 50 shoulder Q were added, and then 0.89 of hydrochloric acid glutamic acid diethyl ester was added, and the following procedure was repeated in the same manner as in Example 17 to prepare HP-glul.

Obtained Og. (Yield 78.1%) Example 19 Diacetylhemadoporphyrin D obtained in Example 16
0.69 glycine ethyl hydrochloride ester was added to 50 g of a Cl4Cl3 solution containing 1 g of CHA salt, and the procedure was repeated in the same manner as in Example 17 to obtain HDA-glyo 99. (Yield 81
．． 1%) Example 20 Diacetylhemadoporphyrin D obtained in Example 16
To a CHCl3 solution 50'IIQ of CHA salt 19 was added 0.89 g of diethyl hydrochloride glutamate, and the same procedure as in Example 17 was carried out to obtain HDA-glul 19.

(Yield 87.3%) Example 21 HP-gly-ethyl ester of the reaction intermediate obtained in Examples 17, 18, 19, and 20.

HP-glu-diethyl ester, HDA-gly-ethyl ester, ODA-glu-diethyl ester, respectively 19,
Add 50 liters of acetic acid to each and dissolve, then 200 liters of sodium acetate.
Add 13,200 mg of Soybean and Inc, and react at 100° C. with stirring. After reaction (can be easily determined by visual inspection, ultraviolet hand scope, and TLC)
, when adding physiological saline 1001112, crystals precipitate,
Collect by filtration, wash the filtered fruits with water, hydrolyze with N/2KOH alcohol, and after the reaction add 10% citric acid to acidify (
When the pH is set to 4), crystals begin to precipitate. Filter this and collect it.
Washed with water and dried to obtain In-HP-gly O,5iF (yield 41.0%).
), In-HP-glu 0.4g (yield 33.3
%), In-HDA-gly O,4y (yield 33.
1%) and I n-HDA-glu O, 49 (yield 33.9
%) were obtained respectively.

Example 22 ■Production of a radioactive diagnostic agent containing a complex of In-monoDTPA-EG Ga-DP as an active ingredient Sterile, pyrogen-free 0.1M citrate buffer (pH 5, 7) 2
xQ to monoD T P A -EG G a-D
Add P 1.96o (1.68 μmol) and dissolve. This solution is passed through a 0.2 μm pore size filter and filled into a nitrogen purged vial. "'InC1 of 1.3mC1
Physiological saline containing 5.0. adding lxQ to the vial;
Target eye' I n-monoD T P A-E
A radioactive diagnostic agent containing a G Ga-DP complex as an active ingredient was obtained.

Example 23 "'In-monoDTPA-EG Properties of a radiodiagnostic agent containing Ga-DP as an active ingredient IIIn-" contained in the radiodiagnostic agent obtained in Example 22
To examine the labeling rate of monoDTPA-EG Ga-DP, a silica gel thin plate was developed using methanol:acetic acid (5:1) as a solvent, and scanned with a radiochromatographic scanner. Radioactivity was depicted as a peak at Rf=0°31, and no other radioactivity peaks were observed. Also,
"' used in the production of the present radiodiagnostic agent shown in Example 22
When chromatography was performed on InC1a in the same manner as above, a radioactive peak was observed at the origin.

From the above results, the "I" contained in this radiodiagnostic agent.
n-mon.

The labeling rate of DTPA-EG Ga-DP is 100
It was confirmed that %.

Example 24 Production of a radioactive diagnostic agent containing a complex of In-HP-gly as an active ingredient.
1 mQ of an acetic acid solution containing -gly 1 , 03i9 (1, 68 μmol) was added, and the mixture was stirred and dissolved for 5 minutes using an ultrasonic cleaner. Furthermore, the solution was heated in an oil bath (80°C) for 1 hour, and then allowed to naturally heat up to room temperature.

Next, 2a(2) of water was added and the mixture was extracted twice with 2m(l) of ethyl acetate.

The ethyl acetate layer was collected, washed with water 2'RQ, and further dried under vacuum. After drying, the residue is 0. lNNaOH0,
05i (2 (5 μmol)) was added, stirred and dissolved, and then 2/15N phosphate buffer (pH 7,4) 2jIρ was added and mixed. This solution was passed through a 0.2 μm pore size filter and filled into a nitrogen-substituted vial. "'In-"
A radioactive diagnostic agent containing an HP-gly complex as an active ingredient was obtained. (Yield 79.4%) Example 25 Properties of a radiodiagnostic agent containing In-HP-gly as an active ingredient IIIn- contained in the radiodiagnostic agent obtained in Example 24
In order to examine the radiochemical purity of HP-gly, a test was conducted in the same manner as in Example 23.

Radioactivity was depicted as a peak at Rf=0.66, and no other radioactivity peaks were observed. From this, it was confirmed that the basic radiochemical purity was almost 100%.

Example 26 ``'In-monoDTPA-EG Scintigraphy of radiodiagnostic agent containing Ga-DP as active ingredient in tumor-bearing hamsters The radioactive diagnostic agent (300 μCi) obtained in Example 22 was statically administered to hamsters transplanted with pancreatic cancer. [Reference Ueda et al.; Peptides, 5, 423. (1984)], and 77 and 96 hours after administration, scintigrams were obtained using a gamma camera equipped with a medium-energy high-resolution collimator. According to this, The cancer site was clearly visualized in both times.This confirmed that the present method is very useful as a cancer diagnostic agent.

Example 27 In-monoDTPA-EG In-body distribution of a radiodiagnostic agent containing Ga-DP as an active ingredient in tumor-bearing hamsters Gallium citrate (117Ga) (1 mCi), which is used as a cancer diagnostic agent in The weight of the organs was measured, and the radioconcentration ratio between the cancer and each organ was obtained.

(The results are shown in Tables 2 and 3) Table 2 "lIn-monoDTPA-EC; G
Distribution of radioactive diagnostic agent containing a-DP as an active ingredient within tumor-bearing hamsters (cancer and each organ at 96 hours after administration Table 3)
Distribution of gallium citrate (6?Ga) within a tumor-bearing hamster (showing the radioactivity ratio between cancer and each organ 72 hours after administration) From Tables 2 and 3, the main rule is that gallium citrate (6?Ga)
It was confirmed that cancer accumulation was higher than in case a).

Example 28 Distribution of a radioactive diagnostic agent containing In-HP-gly as an active ingredient in tumor-bearing hamsters The radioactive diagnostic agent (300 μCi) obtained in Example 24 was intravenously injected into the hamsters shown in Example 26. , dissected in accordance with Example 27,
The radioconcentration ratio of cancer and each organ was obtained. (The results are shown in Table 4).
The radiation concentration ratio of cancer and each organ at 2 hours is shown. ) From Table 4, it was confirmed that the main rule has a high cancer accumulation property.

Example 29 Production of radioactive diagnostic agent containing 89mTc-monoDTPA-EG Ga-DP as an active ingredient MonoDTPA-EG Ga-DP 1.74m
9 (1.5 μmol) in distilled water for injection 1', 5112
0.26 mg (1.5 μmol) of sodium hydrosulfide was added and dissolved with stirring.

Then 0. The pH was adjusted to around 5.7 with IN hydrochloric acid solution. This solution is passed through a 0.2 μm pore size filter and filled into a nitrogen purged vial. 5. Omci Pertechnetate 99mTc-monoD T P A-EG
A radioactive diagnostic agent containing Ga-DP as an active ingredient was obtained.

Example 30 "mTc-monoDTPA-EG Properties of a radiodiagnostic agent containing Ga-DP as an active ingredient"99mTc- contained in the radiodiagnostic agent obtained in Example 29
In order to investigate the labeling rate of monoDTPA-EG Ga-DP, a test was conducted using the same method as in Example 23. Radioactivity is depicted as a peak at Rr = 0.31,
No other radioactivity peaks were observed. Further, when chromatography was performed on the pertechnetate salt used in the production of the present radiodiagnostic agent shown in Example 29 in the same manner as described above, a radioactivity peak was observed at Rr=0.87. From the above results, the “mT” contained in this radiodiagnostic agent
It was confirmed that the labeling rate of c-monoDTPA-EG Ga-DP was almost 100%.

Example 31 Production of a radioactive diagnostic agent containing Ga-DTPA-EG DP-Me as an active ingredient Sterile, pyrogen-free 0.1M citrate buffer (p
H5,7) DTPA-EC; DP-Me on 2 shoulder Q
1.86H (1.68 μmol) is added, dissolved, and then passed through a 0.2 μm pore size filter and filled into a nitrogen-substituted vial. “GaCIJ, 17!12(1
, 3mC1) to the vial to obtain the desired "G"
A radioactive diagnostic agent containing a-DT, PA-EG DP-Me as an active ingredient was obtained.

Example 32 Properties of a radiodiagnostic agent containing Ga-DTPA-EG DP-Me as an active ingredient '7Ga-D contained in the radiodiagnostic agent obtained in Example 31
To investigate the labeling rate of TPA-EG DP-Me,
The test was conducted in the same manner as in Example 23. The radioactivity was depicted as peaks around Rf=0.31 and [=0.06. The radioactivity peak observed at Rf=0.31 is monoDTPA-E GDP-Me, R'
=0.06 are attributed to bisDTPA-EGDP-Me, respectively. This was confirmed from the fact that the Rf on the thin layer had a color characteristic of the derivative. In addition, Example 31
@7GaC1s used in the production of this radiodiagnostic agent shown in
When chromatography was performed using the same method as above, a radioactive peak was observed at the origin. From the above results, the “Ga-DTPA-E” contained in this radiodiagnostic agent
It was confirmed that the labeling rate of GDP-Me was almost 100%.

Example 33 “Production of radioactive diagnostic agent containing Jn-bisDTPA-EG DP as an active ingredient B15DTPA-EG DP 2.41 mg (1
.

68 μM) according to the production method shown in Example 22 to obtain the desired radioactive diagnostic agent containing In-bisDTPA-EGDP as an active ingredient.

Example 34 Properties of a radiodiagnostic agent containing In-bisDTPA-EG DP as an active ingredient 1st In-b contained in the radiodiagnostic agent obtained in Example 33
To investigate the labeling rate of isDTPA-EG DP,
The test was conducted in the same manner as in Example 23. Radioactivity was depicted as a peak near Rf=0.06, and no other radioactivity peaks were observed.

From this, it is clear that the "'I n-bis" contained in this drug is
It was confirmed that the labeling rate of DTPA-EG DP was almost 100%.

Example 35 "Production of a radioactive diagnostic agent containing Ga-HP-glu as an active ingredient" GaC1a (6,62mC1), which was concentrated and dried, was added with H
Add 1 ml of acetic acid solution containing 1.46y (1.68 μmol) of P-glu, and follow the production method shown in Example 24 to obtain the desired radioactive diagnostic agent containing Ga-HP-glu as an active ingredient. (Yield 46.5%)
Example 36 Properties of a radiodiagnostic agent containing Ga-HP-glu as an active ingredient 67Ga-H contained in the radiodiagnostic agent obtained in Example 35
Example 2 To determine the radiochemical purity of P-glu
The test was conducted in the same manner as in 3. The radioactivity is Rf=
A peak was observed at 0.83, and no other radioactivity peaks were observed. From this, it was confirmed that the basic radiochemical purity was almost 100%.

Example 37 2.4-bis[1-(2-hydroxyethyl)oxyethyl] 2 instead of Ga-deuteroporphyrin
,4-bis[1-(3-hydroxypropyl)oxyethyl]Ga-deuteroporphyrin was treated in the same manner as in Example 9 to obtain monoDTPA-PGG.
a-DP was obtained.

Example 38 "Manufacture of a radioactive diagnostic agent containing monoDTPA-PG Ga-DP as an active ingredient" In-mon was processed in the same manner as in Example 22 except that monoDTPA-PG Ga-DP was used.

A radioactive diagnostic agent containing DTPA-PG Ga-DP as an active ingredient was obtained.

Example 39 IIJn-mono DTPA-EG Ga-DP
.

”'In-mono DTPA-PG Ga-DP
Distribution of radioactive diagnostic agents containing gallium citrate (8?G a ) as active ingredients in tumor-bearing and inflammation-inducing hamsters The tumor-bearing hamsters shown in Example 26 were treated with turpentine (Toyo Haika, α-pinene: β-pinene: Q-limonene-8:
1:1 weight ratio) was used to induce inflammation. to this"'
In-mono DTPA-EG Ga-DP (7
60 μCi),”’ I n-mono DTPA-
A radioactive diagnostic agent containing PG Ga-DP (760 u Ci) or gallium citrate (GaX 570 μCi) as an active ingredient was intravenously injected, and 72 hours later, nondigrams were obtained using a gamma camera. Thereafter, dissection was performed over time. The organs were removed, and the radioactivity in each organ and the weight of each organ were measured to obtain the cancer and radioactivity agricultural production ratio of each organ.The results are shown in Table 5.

From the above results, “In-mono DTPA-EG
Ga-DP and “In-mono DTPA-P
GGa-DP shows almost the same ability in terms of cancer affinity and inflammation focus affinity, but gallium citrate (87G a
), both are superior in cancer visualization ability,
It can be understood that the ability to visualize inflammatory foci is inferior.

Example 40 "'In-mono DTP, A-EG Ga-D
Ps"Jn-mono DTPA-PG Ga-D
P, ”'In-mono DTPA-EG Zn
- Biodistribution of radioactive dehydration agents containing DP and gallium citrate (87Ga) as active ingredients in inflammation-induced rats. Croton oil (0 or 1 m) was injected subcutaneously into the right hind paw of SD rats (Body weight 2009). 4 days later, ■'In-m
ono DTPA-EG Ga-DP, ”'In
-mon.

DTPA-PG Ga-DP, “’In-mon.

DTPA-EG Z Rho DP or a radioactive diagnostic agent containing gallium citrate (e?G a ) as an active ingredient (
0°5-1.0 mC1) was administered into the tail vein, and 72 hours later, a scintigram was obtained using a gamma camera. Thereafter, dissection was performed over time, organs were extracted, and the radioactivity in each organ and the weight of each organ were measured to obtain the radioactivity concentration ratio between the cancer and each organ. The results are shown in Table 6.

From the above results, the mouth Jn-mono DTPA-EG
Ga-DP, ”'In-mono DTPA-
PGGa-DP and “In-mono DTPA
-EGZn-DP is gallium citrate (8?Ca)
It can be seen that the degree of accumulation in inflammatory foci is lower than that of 2, and therefore it is more suitable for detecting cancer.

(G) Effects of the Invention Although the radioactive metal-labeled cancer diagnostic agent of the present invention has a high tendency to accumulate in cancer cells, it does not exhibit phototoxicity to normal cells, so it is extremely useful as a cancer diagnostic agent.

Patent applicant: Nippon Mediphysics Co., Ltd. Baka 1

Claims (1)

[Claims] 1. Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R_1 and R_2 are each -CH=CH_
2, -CH_2CH_3, -CH(O-lower alkanoyl)CH_3, -CH(OR)CH_3 or -CH(
O-lower alkylene-OR)CH_3, R^3 is -H,
-COOH, -COO-lower alkyl, -COO-lower alkylene-OR or -COO-lower alkylene-O
OC-Z, R_4 is -H, -lower alkyl or -lower alkylene-OR, R is -H, -lower alkyl or a residue obtained by removing hydrogen from a polyfunctional carboxylic acid, Z is the formula (I
), A is -CH_2-
or -CO-, a dotted line bonded to the γ position indicates no bond or a single bond, and a dotted line between the 7th and 8th positions indicates the presence of a single bond or a double bond. However, R_1, R_2, R_3
And at least one of R_4 must be a group having R representing a polyfunctional carboxylic acid residue. ) A metal complex of a porphine compound represented by A radioactive metal-labeled cancer diagnostic agent containing as an active ingredient a radioactive metal.