Heterodimers and their radiomedical applications

Abstract

This provides a novel, highly specific molecular probe for tumor diagnosis. [Solution] A compound having the structure shown in the following formula (A) is provided. Its use in the preparation of radionuclide labeling or radionuclide labeling reagents is further provided. Furthermore, a radionuclide preparation comprising the compound shown in formula (A) is provided. TIFF2026102884000026.tif67170

Claims

1. A compound represented by the following formula (A). 【Chemistry 1】 (In the formula, The said Z １ is -L １ R １ or -H, and the said Z ２ is -L ２ R ２ or -H, the condition being that the said Z １ is -L １ R １ and / or the said Z ２ is -L ２ R ２ is so, Said L １ Ha- (PEG) ｍ - and the above m is an integer selected from 4 to 30, Said L ２ Ha- (PEG) ｎ - and the above n is an integer selected from 4 to 30, The aforementioned R １ It contains a peptide in which arginine, glycine or sarcosine, and aspartic acid are sequentially linked. The aforementioned R ２ It contains a peptide in which asparagine, glycine or sarcosine, cysteine, and arginine are sequentially linked. The aforementioned R ３ is a group represented by formula (I) or formula (II) below, 【Chemistry 2】 The aforementioned R ４ is a group represented by formula (III), a group represented by formula (IV), or a long-chain fatty acid. 【Transformation 3】 The aforementioned Q １ , the aforementioned Q ２ , the aforementioned Q ３ , the aforementioned Q ４ , and the aforementioned Q ５ These are independently -H, -F, -Cl, -Br, -I, and C. １ -C ６ Linear or branched alkyl, C １ -C ６ Linear or branched fluoroalkyl groups, and C １ -C ６ Selected from the group consisting of linear or branched fluoroalkoxys, The aforementioned x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. The aforementioned y is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6.

2. Said Z １ Ha-L １ R １ L １ Ha- (PEG) ４ - and the above R １ This is a cyclic peptide shown in SEQ ID NO: 1 or 2, Said Z ２ Ha-L ２ R ２ L ２ Ha- (PEG) ４ - and the above R ２ This is a cyclic peptide represented by one of sequence numbers 3 to 6, The aforementioned R ３ is a group represented by the following formula (L-I), a group represented by the formula (D-I), a group represented by the formula (L-II), or a group represented by the formula (D-II), where x is 3. 【Chemistry 4】 The aforementioned R ４ is a group represented by the above formula (III), where y is 2 or 3, The aforementioned Q １ is -H, and the above Q ２ is -H, and the above Q ３ Ha-CF ３ or -I, and the above Q ４ is -H or -F, and the above Q ５ is -H or -F. The compound according to claim 1.

3. The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 2, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-I), and the Q ３ -I, the above Q ４ -H, the above Q ５ ga -H, and y is 3, said R １ is the cyclic peptide shown in SEQ ID NO: 1, said R ２ is the cyclic peptide shown in SEQ ID NO: 4, said R ３ is the group represented by formula (L-I), said Q ３ is -CF ３ said Q ４ is -H, said Q ５ is -H, and y is 3, said R １ is the cyclic peptide shown in SEQ ID NO: 1, said R ２ is the cyclic peptide shown in SEQ ID NO: 4, said R ３ is the group represented by formula (L-I), said Q ３ is -CF ３ said Q ４ is -F, said Q ５ is -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 4, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 5, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 5, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 5, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (D-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (D-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (D-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (D-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (D-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (D-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 2, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 2, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 2, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 2, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 2, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 2, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (L-I), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (L-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (L-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (L-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (L-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (D-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (D-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 3, the R ３ The base is represented by formula (D-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (D-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -H, and y is 3, The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (D-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -F, the aforementioned Q ５ If -H, and y is 3, or The aforementioned R １ The cyclic peptide shown in Sequence ID No. 1, the R ２ The cyclic peptide shown in Sequence ID No. 6, the R ３ The base is represented by formula (D-II), and the Q ３ ga-CF ３ , the aforementioned Q ４ -H, the above Q ５ ga -F, and the above y is 3, The compound according to claim 1.

4. A compound according to any one of claims 1 to 3, A radionuclide chelated with the aforementioned compound, A radioactive nuclide preparation containing [the specified substance].

5. The aforementioned radioactive nuclides are, ４４ Sc, ４７ Sc, ６２ Cd, ６４ Cd, ６７ Cd, ６６ Ga, ６７ Ga, ６８ Ga, ８６ Y, ９０ Y, ８９ Zr, ９９ｍ Tc, １１０ｍ In, １１１ In, １１３ｍ In, １１４ｍ In, １７７ Lu, １８８ Re, ２０３ Pb, ２１２ Pb, ２１２ Bi, ２１３ Bi, ２１１ At, ２２３ Ra and ２２５ The radionuclide preparation according to claim 4, wherein at least one selected from the group consisting of Ac.

6. A method for preparing the compound according to any one of claims 1 to 3, The steps include obtaining a first compound represented by the following formula (A1), 【Transformation 5】 The steps include obtaining a second compound represented by the following formula (A2), 【Transformation 6】 -N*H of the second compound ２ A group and the compound represented by the following formula (I') or the compound represented by the following formula (II') or its -N*H ２ The steps include: obtaining a third compound having a group represented by the following formula (I'') or a group represented by the following formula (II'') by forming an amide bond with the -C*OOH group of a protected compound; 【Transformation 7】 The steps include reacting the third compound with the first compound to obtain a fourth compound, The group represented by formula (I'') or the group represented by formula (II'') of the fourth compound -N*H ２ The steps include: forming an amide bond between the group and the -C*OOH group of the compound represented by the following formula (III'), 【Transformation 8】 A preparation method including the following.

7. A pharmaceutical composition used for radionuclide labeling, cancer detection, cancer diagnosis, cancer progression monitoring, cancer treatment monitoring, or cancer treatment, comprising a compound according to any one of claims 1 to 3.

8. A pharmaceutical composition used for radionuclide labeling, cancer detection, cancer diagnosis, cancer progression monitoring, cancer treatment monitoring, or cancer treatment, comprising the radionuclide preparation described in claim 4.

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