Folate receptor targeting radioactive folate derivative and preparation method and application thereof

Abstract

The invention provides a folate receptor targeting radioactive folic acid derivative and a preparation method and application thereof, and relates to the technical field of radiolabeling. A first aspect of the invention provides a folate receptor targeting radioactive folate derivative, the radioactive folate derivative has a structure as shown in a formula 1, and radionuclide is one of 68Ga, 64Cu, Al18F, 89Zr and 177Lu. The radioactive folic acid derivative provided by the invention can be prepared into an injection for PET diagnosis or treatment of tumor of a targeted folate receptor, is lowin preparation cost, and has the advantages of high labeling rate, strong in-vivo stability and the like.

Description

technical field [0001] The invention relates to the technical field of radiolabelling, in particular to a radioactive folic acid derivative targeting folic acid receptors, a preparation method and application thereof. Background technique [0002] Folic acid (Folic Acid, FA) is pteroyl glutamic acid, which participates in important processes such as methionine cycle, methylation reaction, and DNA synthesis in organisms. Folic acid is necessary for mammalian cells but cannot be synthesized by itself, so it must be completely dependent on exogenous supply. Folate Receptor (FR) is a glycosylphosphatidylinositol (GPI)-coupled protein, except for individual tissues, the expression level of folate receptor FR is very low in normal tissues, while in many tumor cells surface overexpression. Folate receptors have high affinity and specificity with folic acid and its derivatives, such as methyltetrahydrofolate, etc. Based on this characteristic, imaging agents, therapeutic drugs, et...

AI Technical Summary

Problems solved by technology

[0004] Nuclides currently used to label FR-targeted radiopharmaceuticals include 18 F. 67 / 68 Ga, 99m Tc, 111 In etc., among them, 67 The application of Ga-labeled folic acid chelates to imaging of human folate receptor-positive tumors was earlier, but so far no related drugs have been studied in preclinical studies (Ke, CY, Mathias CJ, Green MA, Adv Drug Deliver Rev, 2004.56:1143-1160); 111 In-DTPA-FA is the first FR-targeted tumor imaging agent to enter and complete phase II clinical trials, but due to 111 In is not easy to prepare, expensive, and has a long half-life (t1 / 2=68h), so it has not really entered clinical use [Siegel BA, Dehdashti F, Mutch DG, etc.J Nucl Med.2003.44(5):700-707 .]; 99m The source of Tc is convenient, the price is cheap, and the half-life is short (t1 / 2=6.02h). It can be injected in a large dose to obtain images with a high labeling rate, and the radiation dose to the human body is small. In recent years, more studies have been made on 99m Tc-labeled folic acid chelate, wherein, 99m Tc(CO) 3 -DTPA-folate has a higher specific activity than 111 In-DTPA-Folic Acid and 99m Tc-DTPA-folate (Mathias CJ, Hubers D, LowPS, etc. Bioconjug Chem. 200011:253-257.), 99m Tc-EC20 (Müller C, Reddy JA, Leamon CP, etc. Mol Pharm. 2010, 7: 597-604.) is one of many 99m Research hotspots in Tc-based imaging agents, and with the birth of click chemistry [ 99m Tc(CO) 3 (H 2 O) 3 ]-based on 99m Folic acid labeling of Tc has also appeared (Mindt TL, Müller C, Melis M, etc. Bioconjug Chem.2008 19:1689-1695); but the above nuclides are all single-photon nuclides, and the labeling rate of imaging is relatively low

and 67 / 68 Ga-DOTA-folate (Fani M, Wang X, Nicolas G, etc. Eur J Nucl MedMol Imaging.2011 38:108-119.) is greatly limited in clinical application due to poor stability in vivo

At the same time the radionuclides 18 The use of direct nucleophilic substitution followed by hydrolysis to prepare new folic acid molecular probes has also emerged (Ross TL, Honer M, Müller C, etc. J Nucl Med. 2010 51:1756-1762.), however, due to radiochemical yields only 4%, which greatly limits the application of clinical transformation and is currently limited to laboratory research

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