KR101635989B1 - Novel compounds comprising a bombesin derivative, a process for the preparation thereof and a nuclear molecular imaging agent comprising the same - Google Patents

Abstract

The present invention relates to a novel compound having a structure in which a bombesin derivative known to have selectivity for prostate cancer and the like binds to a ligand via aminomethylgalacturonic acid, a ligand of the novel compound, a radioisotope and a coordination complex compound, Methods for their preparation, and nuclear medicine molecular imaging contrast agents comprising the complexes.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel compound containing a bombesin derivative, a method for producing the same, and a contrast agent for a nuclear medicine molecular image including the compound, a process for preparing the same and a nuclear molecular imaging agent comprising the same,

The present invention relates to a novel compound comprising a bombesin derivative, a process for producing the same, and a contrast agent for nuclear medicine molecular imaging including the compound.

It has been reported that the method of diagnosing and treating the cell after labeling the peptide with a radioactive isotope for a receptor on the surface of a malignant cell such as a tumor cell has high selectivity and efficiency for the diagnosis and treatment of the tumor. In addition, the advantage of peptides to receptors present in these malignant cells is that they have a high selectivity for normal tissues and that peptides are relatively small in size compared to antibodies and therefore have a characteristic of rapidly binding to receptors in the body.

Studies and discoveries of peptides for diagnosis and treatment using radioisotopes have been actively conducted worldwide, and representative radioisotope-labeled peptides that have been discovered and studied so far are summarized in Table 1 below (Non-Patent Document 1).

Gastrin releasing peptide (GRP) is a kind of peptide having physiological activity such as promoting secretion of gastrin or pancreatic enzyme and cell proliferation. Major molecular type is composed of 27 amidated amino acid residues at C-terminal , And the bombesin-like family (BBN). In mammals, like gastrin, they are not secreted from mucosal endocrine cells but secrete from neurons. These GRPs stimulate the proliferation and invasion of cancer cells in androgen-independent prostate cancers, and the expression of GRP receptor mRNA is measured in 90% of patients with prostate cancer, and human prostate cancer cells PC-3 , DU-145, and LNCaP cells were also reported to express GRP receptors.

Non-patent document 2 summarizes research on the use of bombesin derivatives for the diagnosis or treatment of cancers by marking radioactive isotopes. It was reported that prostate cancer bombesin analogues (Bombesin-analogues) by using of a ^99m Tc-RP527 is ^99m Tc labeling the RP527 original cancer and bone from patients with metastases imaging of cancer, ^[99m Tc] - and ^[68 Ga] - A marker BBN peptide was used to diagnose metastatic prostate cancer, breast cancer and gastrointestinal stromal tumor. Furthermore, using human prostate carcinoma model in mice showed a high uptake rate of ⁶⁸ Ga a gastrin release peptide in 9.5% ID / g when obtaining a biometric image in PET after labeling, the radioisotope AMBA (Bombesin-like peptide) After tumor marker ¹⁷⁷ Lu was labeled, the tumor targeting ability in the test animal was observed with mciroSPET / CT. The tumor image was acquired by molecular imaging and the distribution of ¹⁷⁷ Lu-AMBA was measured. Most clinical studies have been done with SPECT and ¹¹⁷ Lu radioisotopes have been used to treat patients with prostate cancer. Table 2 summarizes the current state of research.

Researcher Nuclide BBN derivative Dose (MBq) peptide mass Number of patients Van de Wiele et al. ^99m Tc (SPECT) RP527 555 3 ng / kg 4AI De Vincentis et al. ^99m Tc (SPECT) [Leu13] BN 185 0.7ug 1AD Scopinaro et al. ^99m Tc (SPECT) [Leu13] BN 185 0.7ug 8AD De Vincentis et al. ^99m Tc (SPECT) [Leu13] BN 185 0.7ug 12AD Bodei et al. ¹⁷⁷ Lu (SPECT) AMBA 1140-1940 - 7AI Hofmann et al. ⁶⁸ Ga (PET) DOTABOM 26-80 24 nmol 11AD

AI, androgen independent; AD, androgen dependent

Thus, studies on the use of bombesin derivatives for the diagnosis or treatment of cancer have been actively conducted by labeling radioactive isotopes with the radioisotope, but most of the peptides for radioactive isotope labeling are high in consumption by the liver and low in consumption by the tumor, There is a possibility of misunderstanding.

1. Journal of Nuclear Medicine, 52 (12), 2011 2. R.P.J. Schroeder et al. / Methods 48 (2009) 200-204

An object of the present invention is to provide a novel peptide compound for labeling radioactive isotopes for cancer diagnosis by nuclear medicine molecular imaging, which has a low uptake rate by the liver and high selectivity for cancer tissues.

Another object of the present invention is to provide a method for producing the novel peptide compound.

Another object of the present invention is to provide a complex in which a radioactive isotope for cancer diagnosis is labeled on a novel peptide compound for labeling a radioactive isotope for cancer diagnosis by nuclear medicine molecular imaging with a low intake rate by the liver and high selectivity for cancer tissue .

It is a further object of the present invention to provide a contrast agent for nuclear medicine molecular imaging comprising the complex.

In order to achieve the above object,

The present invention provides a compound of formula 1 wherein the bombesin (BBN) derivative is coupled to the ligand via aminomethyl galacturonic acid:

[Chemical Formula 1]

The bombesin (BBN) derivative comprises a peptide of Gln-Trp-Ala-Val-Gly-His-Leu-Met sequence and binds to a GRP (Gastrin Releasing Peptide) receptor, wherein the carboxyl- Amide bond with the carboxyl group of methyl galacturonic acid,

The ligand is DOTA, DTPA, DO3A, NOTA, NODAGA, TETA, TE3A, TE2A, or PCTA, and the carboxyl group of the ligand forms an amide bond with the amino group of the aminomethyl galacturonic acid.

Another aspect of the present invention provides a compound of formula 2 wherein the ligand of the compound of formula 1 is coordinately bound to a radioactive isotope X:

(2)

In Formula 2, X is a radioisotope capable of SPECT or PET measurement.

Another aspect of the present invention is

Reacting the bombesin derivative with aminomethylgalacturonic acid to amide bond the carboxyl group at the terminal of the peptide to the carboxyl group of aminomethylgalacturonic acid; And

Comprising reacting aminomethyl galacturonic acid with a ligand to amide bond the amino group of the aminomethyl galacturonic acid with the carboxyl group of the ligand.

Another aspect of the present invention provides a SPECT contrast agent for cancer diagnosis comprising the compound of formula (2).

Another aspect of the present invention provides a PET contrast agent for cancer diagnosis comprising the compound of formula (2).

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

The inventors of the present invention have solved the problem that the contrast agent for diagnosing or treating cancer in which a ligand bound to a bulbous derivative is labeled with a radioactive isotope has a low selectivity for cancer tissue and high intake by the liver, . As a result, when a novel peptide compound was prepared by introducing galacturonic acid as a linker between a bombesin derivative and a radioisotope labeling ligand, it was found that the radioactive isotope labeling showed high selectivity for cancer cells (Experimental Example 3 ), And it was confirmed to be stable in blood for a sufficient time required for nuclear medicine molecular imaging in blood (Experimental Example 2). In addition, when the new peptide compound was actually administered to a mouse of a prostate cancer model and the PET image was taken, the tumor uptake rate was relatively high and the liver uptake rate was relatively low compared to the case where galacturonic acid was not included as a linker (Experimental Example 4).

Accordingly, in one aspect of the present invention,

The present invention provides a compound of formula 1 wherein the bombesin (BBN) derivative is coupled to the ligand via aminomethyl galacturonic acid:

[Chemical Formula 1]

The bombesin (BBN) derivative comprises a peptide of Gln-Trp-Ala-Val-Gly-His-Leu-Met sequence and binds to a GRP (Gastrin Releasing Peptide) receptor, wherein the carboxyl- Amide bond with the carboxyl group of methyl galacturonic acid,

The ligand is DOTA, DTPA, DO3A, NOTA, NODAGA, TETA, TE3A, TE2A, or PCTA, and the carboxyl group of the ligand forms an amide bond with the amino group of the aminomethyl galacturonic acid.

The compound of Formula 2 may be prepared by coupling a ligand of the compound of Formula 1 with a radioactive isotope for nuclear medicine molecular imaging to form a complex. Accordingly, in another aspect, the invention provides compounds of formula 2:

(2)

In Formula 2,

Wherein the bombesin derivative and the ligand are as defined in Formula 1,

X is a radioactive isotope that enables SPECT or PET measurement and is coordinated to the ligand.

In the present specification, "ligand → X" means a complex formed by coordinating a radioisotope X with the ligand.

As used herein, the term "complex" refers to a group of atoms consisting of several different atoms, ions, molecules or atoms centered on one or more atoms or ions in a directionally coordinated manner . Here, atomic ion molecules (chelator) or atomic group coordinated to a central atom or ion are called a ligand.

Tetraazacyclododecane-1,4,7,10-tetraacetic acid, DTPA is diethylene triamine penta aeetic acid, DO3A is 1,4,7,10-tetraazacyclododecane-1, 4,7-triacetic acid, NOTA is 1,4,7-triazacyclononane-1,4,7-triacetic acid, NODAGA is 1,4,7-triazacyclononane, 1-glutaric acid-4,7-acetic acid, TETA 1,4,8,11-tetraazacyclotetradecane-1,4,8-triacetic acid, TE2A, and tetraazacyclotetradecane-N, N ' 1,4,8,11-Tetraazabicyclohexadecane-4,11-diacetic acid, PCTA is 3,6,9,15-tetraazabicyclo [9.3.1] pentadeca- 1,11,13-triene- Triacetic acid is a metal-compatible ligand compound. The ligand acts as a ligand of a metal-affinity ligand so that the radioactive isotope can be prevented from being released in the body and the cytotoxicity due to the radioactive substance can be reduced because the radioactive substance is removed from the body. Therefore, (Marouan Rami et al., Carbonic anhydrase inhibitors: Gd (III) complexes of DOTA- and TETA-sulfonamide conjugates targeting the tumor associated carbonic anhydrase isozymes IX and XII, New J. Chem., 2010, 34, 2139 (1998) Volume: 36, Issue: S1, Pages: S200-S208). The NMR spectrometry of Gd (III) complexes with heptadentate macrocyclic ligands, Silvio Aime et al.

As used herein, the radioactive isotope "X" is a radioactive isotope for nuclear medicine molecular imaging, specifically, any isotope capable of measuring SPECT or PET. For example, X is radioiodine, Tc-99m, Re-188, Re-186 and Lu-177 selected from I-123, I-124, I-125 and I-131 as isotopes for SPECT measurement And may be Cu-64, Cu-67, Ga-68, or Zr-89 as isotopes for PET measurement. According to one embodiment, the radioisotope is ⁶⁴ Cu.

 As used herein, the term " bombesin (BBN) derivative "includes peptides of the Gln-Trp-Ala-Val- Gly-His-Leu-Met sequence and includes any peptide that binds to the GRP (Gastrin Releasing Peptide) do. The Gln-Trp-Ala-Val-Gly-His-Leu-Met sequence is an active fragment of bombesin, and the bombesin derivative contains an active fragment of bombesin to be specific for prostate cancer, breast cancer, (Non-Patent Document 2). The bombesin derivative is not expressed in normal tissues and binds to a GRP receptor expressed in specific cancer cells such as prostate cancer and breast cancer, thereby enabling a target for cancer tissue. Therefore, the compound of Formula 2 is useful for diagnosing cancer Can act as an effective contrast agent.

The bombesin derivative may contain additional amino acid sequences in addition to the Gln-Trp-Ala-Val-Gly-His-Leu-Met sequence provided that the above conditions are satisfied. Those skilled in the art will be able to prepare Bombesin derivatives that satisfy the above conditions from knowledge known in the art. According to one embodiment, the bombesin derivative is composed of a peptide of Gln-Trp-Ala-Val-Gly-His-Leu-Met.

The compound of formula 2 may, according to one embodiment, be a compound of formula 2a:

(2a)

According to another aspect of the present invention,

Reacting the bombesin derivative with aminomethylgalacturonic acid to amide bond the carboxyl group at the terminal of the peptide to the carboxyl group of aminomethylgalacturonic acid; And

Comprising reacting an aminomethyl galacturonic acid with a ligand to amide bond the amino group of the aminomethyl galacturonic acid and the carboxyl group of the ligand to the compound of Formula 1 or 2:

The bombesin derivatives and ligands are as defined in the above formula (1) or (2).

The amide bond of the bombesin derivative and aminomethyl galacturonic acid can be carried out by those skilled in the art of organic chemistry using knowledge known in the art. Amide bond of aminomethylgalacturonic acid and a ligand can also be performed by those skilled in the art of organic chemistry using knowledge known in the art.

The bombesin derivatives constituting the compounds according to Formula 1 or Formula 2 can be prepared by peptide-bonding amino acids by the Fmoc solid phase synthesis method known in the art. The preparation of peptides by Fmoc solid phase synthesis is well known in the art and one skilled in the art can select appropriate reaction conditions to produce bombesin derivatives.

The compound of Formula 2 may be prepared by reacting a compound of Formula 1 with a radioactive isotope to form a complex with a ligand of the compound of Formula 1.

The compound of formula (1) can also be prepared by the Fmoc solid phase synthesis. Specifically, the compound of Formula 1 can be synthesized by Fmoc solid phase synthesis using aminomethylgalacturonic acid, a ligand, and an amino acid unit as a reactant.

The compound of Formula 2 was found to be highly selective for cancer cells when labeled with radioactive isotopes (Experimental Example 3), and was found to be stable in blood for a sufficient time required for nuclear medicine molecular imaging in blood (Experimental Example 2 ). In addition, when the novel peptide compound is actually administered to a mouse of a prostate cancer model and a nuclear medicine molecular image is taken, the rate of tumor uptake is relatively high while the rate of liver uptake is relatively low compared to the case of not containing galacturonic acid as a linker (Experimental Example 4). Thus, it has been found that the compound of formula 2 can be effectively used as a nuclear medicine molecular imaging contrast agent such as SPECT or PET.

Accordingly, in another aspect, the present invention provides a SPECT contrast agent comprising the compound of Formula 2 or Formula 2a.

Accordingly, in another aspect, the present invention provides a PET contrast agent comprising the compound of Formula 2 or Formula 2a.

Since the SPECT contrast agent or PET contrast agent according to the present invention is selective for cancer cells expressing GRP receptors, it can be used for diagnosis of breast cancer and prostate cancer, which are known to express GRP receptors. In addition, since the rate of tumor uptake in the liver is high and liver uptake is low, it can be used as an effective contrast agent for the diagnosis of tumors.

The SPECT contrast agent can be administered to an adult at a dose of 0.5-1 mCi / kg based on the compound of formula (2), which is the active ingredient.

The PET contrast agent may be administered to an adult in an amount of 0.5-1 mCi / kg based on the compound of formula (2) as the active ingredient.

The SPECT contrast agent or PET contrast agent according to the present invention may be formulated as an injectable preparation. When the composition is formulated into an injection, a non-toxic buffer solution that appears as blood may be contained as a diluent. For example, a phosphate buffer solution of pH 7.4 may be used . The MRI contrast agent may include other diluents or additives in addition to the buffer solution. Excipients and additives that may be added to such injections are well known to those skilled in the art and can be found, for example, in the following references: Dr. HP Fiedler "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete "[Encyclopedia of auxiliaries for pharmacy, cosmetics and related fields]).

As described above, the compound of formula (2) or (2a) according to the present invention contains a bombesin derivative having a high affinity for binding to GRP receptors, and thus can be used for specific and safe nuclear medicine molecular imaging for specific cancers such as breast cancer and prostate cancer. Can be used as a contrast agent. In addition, the compound of formula (2) or (2a) contains a galacturonic acid structure, so that the rate of uptake by the liver is lowered, thereby enabling accurate diagnosis of cancer.

Figure 1 shows the formulas of NODAGA-BBN and NODAGA-galacto-BBN.
Figure 2 shows the chemical formulas of [ ⁶⁴ Cu] NODAGA-BBN and [ ⁶⁴ Cu] NODAGA-galacto-BBN.
3 is a graph of HPLC analysis of NODAGA-BBN.
FIG. 4 is a mass analysis graph of NODAGA-BBN using a MALDI TOF apparatus.
FIG. 5 is a graph of HPLC analysis of NODAGA-Galacto-BBN prepared according to one embodiment of the present invention.
FIG. 6 is a mass spectrometry graph of a NODAGA-Galacto-BBN prepared according to an embodiment of the present invention using a MALDI TOF instrument.
7 is ⁶⁴ Cu, ^[64 Cu] is NODAGA-BBN and TLC-Radio (Radio-thin layer chromatography) the image of the ^[64 Cu] -BBN NODAGA- galactosidase prepared according to one embodiment of the invention.
8 is a graph showing a result of measuring the stability of the ^[64 Cu] NODAGA-BBN and one embodiment the ^[64 Cu] human serum and in mouse serum NODAGA- -BBN galactosidase prepared according to the present invention.
FIG. 9 is a graph showing the specific binding activity of NODAGA-BBN and NODAGA-galacto-BBN prepared according to one embodiment of the present invention to human prostate cancer cell line PC3 cells.
10 is ^[64 Cu] NODAGA-BBN or prepared according to one embodiment of the present invention ^[64 Cu] NODAGA- after injection of the human prostate cancer cell line galactosyl -BBN (PC3 cells) tumor model mouse taken PET image to be.
Figure 11 shows the effect of [ ⁶⁴ Cu] NODAGA-BBN on a human prostate cancer cell line (PC3 cell) tumor model mouse or in a PET image taken after [ ⁶⁴ Cu] NODAGA-galacto-BBN injection prepared according to one embodiment of the present invention Liver uptake, and tumor / muscle uptake.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, these examples and experimental examples are provided to aid understanding of the present invention, and the scope of the present invention is not limited thereto in any sense. Abbreviations used herein are the same as commonly used in the art unless otherwise specifically defined herein.

Definitions of Abbreviations in the Examples

NODAGA-BBN: a compound in which NODAGA and Gln-Trp-Ala-Val-Gly-His-Leu-Met peptide, an active fragment of the bombesin peptide,

Val-Gly-His-Leu-Met peptide, an active fragment of NODAGA-galacto-BBN: NODAGA, aminomethylgalacturonic acid, and bombesin peptide,

[ ⁶⁴ Cu] NODAGA-galacto-BBN: Complexes in which ⁶⁴ Cu is coordinated to NODAGA of NODAGA-galacto-BBN

SPPS: solid phase peptide synthesis

HPLC: High Performance Liquid Chromatography

TFA: Trifluoroacetic acid

ACN: acetonitrile

RT: Retention time

Radio TLC: radio-thin-layer chromatography

BSA: bovine serum albumin

Preparation Example 1: Preparation of NODAGA-BBN and NODAGA-galacto-BBN

NODAGA-BBN and NODAGA-galacto-BBN having the structures shown in FIG. 1 were synthesized by the Fmoc-based SPFT (Solide-phase peptide synthesis) method using a PIT-Symphony peptide synthesizer.

The prepared NODAGA-BBN and NODAGA-galacto-BBN were analyzed by HPLC. An ACN solution (solution B) of 0.1% TFA aqueous solution (A solution) and 0.1% TFA was added at a concentration of 5% to 65% B for 1 hour to 30 mL / min using SHIMADZU C-18 analytical column (10.0 mm x 250 mm) min, the peak can be identified at RT 19.183 min (NODAGA-BBN), RT 19.783 min (NODAGA-galacto-BBN). The results are shown in FIGS. 3 and 5. In addition, the NODAGA-BBN and NODAGA-galacto-BBN prepared were analyzed by MALDI-TOF-MS, and the results are shown in FIGS.

Figure 3 is an HPLC image of the NODAGA-BBN produced and Figure 4 is a MALDI-TOF-MS image of the NODAGA-BBN produced.

Figure 5 is an HPLC image of NODAGA-galacto-BBN prepared according to one embodiment of the present invention, and Figure 6 is a MALDI-TOF-MS image of NODAGA-galacto-BBN prepared according to one embodiment of the present invention to be.

Production Example 2: [ ⁶⁴ Cu] NODAGA-BBN and [ ⁶⁴ Cu] NODAGA-galacto-BBN

24 μL of a solution of NODAGA-BBN or NODAGA-galacto-BBN prepared by dissolving NODAGA-BBN or NODAGA-galacto-BBN prepared in Preparation Example 1 in 1 M sodium acetate at a concentration of 1 mg / mL was added to a sodium acetate And mixed with 1 mL of buffer. Sodium acetate buffer solution of pH 4 was prepared by first diluting stock solution A [11.55 ml of glacial acetic acid (CH ₃ COOH) in distilled water to prepare 0.2 M 1 L solution] and Stock solution B [16.41 g of anhydrous sodium acetate (CH ₃ COONa) Or 7.22 g of CH ₃ COONa-3 H ₂ O diluted in distilled water to prepare a 0.2 M 1 L solution], and then mixed with 296 μL (stock solution A) and 704 μL (stock solution B), respectively. Thereafter, the cells were reacted with ⁶⁴ Cu (pH 4 sodium acetate buffer / 200 μL) at 9.2-74 MBq (0.5-2 mCi) at 70 ° C for 10 minutes. After the reaction, radio-TLC was used to confirm the radiochemical yield of the final product.

The structural formulas of [ ⁶⁴ Cu] NODAGA-BBN and [ ⁶⁴ Cu] NODAGA-galacto-BBN prepared are shown in FIG.

Experimental Example 1: ⁶⁴ Determination of the radiochemical yield of NODAGA-BBN and NODAGA-galacto-BBN using Cu

Radical chemical yields of [ ⁶⁴ Cu] NODAGA-BBN and [ ⁶⁴ Cu] NODAGA-galacto-BBN prepared in Preparation Example 2 were analyzed using Radio TLC. The results are shown in FIG.

According to FIG. 7, the radiochemical yield of [ ⁶⁴ Cu] NODAGA-BBN and [ ⁶⁴ Cu] NODAGA-galacto-BBN was confirmed to be 100% after reaction at ⁶⁴ ° C and 70 ° C for 10 minutes.

Experimental Example 2: ⁶⁴ Cu] NODAGA-BBN and [ ⁶⁴ Cu] NODAGA-galacto-BBN

Human serum, mouse serum, physiological saline, and [ ⁶⁴ Cu] NODAGA-BBN or [ ⁶⁴ Cu] NODAGA-galacto-BBN were mixed in order to confirm serum stability. The stability of the final product was confirmed using radio-TLC at specific times while reacting for 24 hours.

The results are shown in Fig.

According to the data in FIG. 8, [ ⁶⁴ Cu] NODAGA-BBN and [ ⁶⁴ Cu] NODAGA-galacto-BBN were stable for up to 2 hours in human serum and mouse serum, and were stable for 24 hours in physiological saline.

Experimental Example 3: Comparison of cell binding ability to human prostate cancer cell line (PC3)

The binding ability of NODAGA-BBN and NODAGA-galacto-BBN synthesized in Preparation Example 1 to PC3 cells was compared. As a control, [ ¹²⁵ I] TryI 4-BBN (Perkinelmer Co. MA) was used.

PC3 cells ^{(2X10 6) 0.06 nM [125} I] Try4-BBN (NEX258050UC, PerkinElmer Co. MA) and (Lactobacillus -BBN go NODAGA-BBN or NODAGA-) substance of various concentrations (1.00-E4 ~ 1.00-E13M ) in Were added to the binding buffer and reacted for 1 hour with stirring at room temperature. The binding buffer was prepared by mixing 25 mM Tris pH 7.4, 150 mM NaCl, 1 mM MnCl ₂ and 0.1% BSA (bovine serum albumin). After the completion of the reaction, the radioactivity remaining in each tube was measured with a gamma counter (PerkinElmer Co. MA) after washing 2 times with 3 ml of PBS (Phosphate buffed saline). IC ₅₀ values were obtained by nonlinear regression using GrasphPad Prism (GraphPad Software, Inc., CA).

The results are shown in Fig.

Referring to Figure 9, the value of the Lactobacillus -BBN go NODAGA-BBN and NODAGA- is (5.47 ± 0.38) X10 ⁷ and (6.67 ± 1.07) indicated by X10 ⁸ mol / L, PC3 cells NODAGA- galactosyl each -BBN BDNF was significantly higher than that of NODAGA-BBN.

Experimental Example 4: In vivo PET image acquisition in human prostate cancer cell line (PC3) tumor model mouse

The target effect of the [ ⁶⁴ Cu] NODAGA-BBN or [ ⁶⁴ Cu] NODAGA-galacto-BBN prepared in Preparation Example 2 on the human prostate cancer cell line (PC3) tumor model was confirmed. BALB / c-nu / nu mice (male, about 6 weeks old, weight 20-25g) (NarabioTec, Seoul, Korea) or NOD.CB17-Prkdc ^scid mouse using the (male, about 6 weeks old, weight 20-25g) Human prostate cancer cell line (PC3) tumor model was constructed. A human prostate cancer cell line (PC3) tumor model was prepared by subcutaneously injecting human prostate cancer cell line (PC3) into the left or right hind part of the mouse at a concentration of 5 × 10 ⁶ cells.

[ ⁶⁴ Cu] NODAGA-BBN or [ ⁶⁴ Cu] NODAGA-galacto-BBN of 16.7-18.5 MBq (450-500 μCi) was injected intravenously through the tail vein of anesthetized anesthetized via 2% isofluorane PET images were taken 1, 2, and 4 h after injection for 60 min. The results are shown in Fig.

Referring to Figure 10, 1, 2, and 4 hours from the image ^[64 Cu] NODAGA- galactosidase when the injection of ^[64 Cu] NODAGA-BBN in the group injected with -BBN between intake significantly lower than (liver uptake ) And showed a significantly higher tumor to muscle ratio at 1, 2, and 4 h in the [ ⁶⁴ Cu] NODAGA-galacto-BBN injected group.

Claims (11)

delete delete delete delete delete delete delete Compounds having the structure of formula
(2a)

A PET contrast agent for cancer diagnosis comprising the compound according to claim 8. 10. The PET contrast agent according to claim 9, wherein the cancer is prostate cancer, breast cancer, pulmonary small cell carcinoma, stomach cancer or neuroblastoma. delete

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