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2-<18>F-fluoropropionic acid isomers, synthesis method and application thereof

A technology of S-18F-FPA and R-18F-FPA is applied in the application field of preparing positron emission tomography imaging agent drugs, which can solve the problem of difficult synthesis of chiral compounds, high difficulty of automatic synthesis, poor stereoselectivity, etc. problem, to achieve the effect of excellent pharmacokinetic properties

Inactive Publication Date: 2017-09-01
GUANGDONG HUIXUAN PHARMA TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Purpose of the present invention is exactly in order to overcome current 2- 18 F-fluoropropionic acid ( 18 F-FPA) racemic mixture has poor stereoselectivity in pharmacodynamics, pharmacokinetics, toxicology, etc., providing a stable in vivo non-defluorination, with the same 11 Excellent pharmacokinetic properties similar to C-AC, and a highly sensitive and specific optically active PET imaging agent, namely 2- 18 F-fluoropropionic acid chiral enantiomer: R-2- 18 F-fluoropropionic acid (R- 18 F-FPA) and S-2- 18 F-fluoropropionic acid (S- 18 F-FPA)
[0008] The present invention also overcomes the difficulty in the synthesis of chiral compounds, especially the difficulty in the automatic synthesis of chiral radiopharmaceuticals, and provides a simple 2- 18 F-fluoropropionic acid chiral isomer: R-2- 18 F-fluoropropionic acid (R- 18 F-FPA) and S-2- 18 F-fluoropropionic acid (S- 18 The radiochemical synthesis method of F-FPA)

Method used

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  • 2-&lt;18&gt;F-fluoropropionic acid isomers, synthesis method and application thereof
  • 2-&lt;18&gt;F-fluoropropionic acid isomers, synthesis method and application thereof
  • 2-&lt;18&gt;F-fluoropropionic acid isomers, synthesis method and application thereof

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Experimental program
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Embodiment 1

[0029] 1.1 Synthetic route

[0030] 2- of the present invention 18 F-fluoropropionic acid ( 18 Enantiomer of F-FPA): R-2- 18 F-fluoropropionic acid (R- 18 F-FPA) and S-2- 18 F-fluoropropionic acid (S- 18 F-FPA), using S- or R-2-trifluoromethanesulfonate ethyl propionate as a precursor respectively, can realize its fully automatic synthesis through two-step reactions of nucleophilic fluorination and column hydrolysis. S- or R-ethyl 2-trifluoromethanesulfonate propionate, in catalyst 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8,8,8 ] Hexadecane (Kryptofix2.2.2, K222) under the action, and [K / K222] +18 f - A fluorination reaction occurs to generate the intermediate R-2- 18 F-Ethyl fluoropropionate or S-2- 18 F-Ethyl fluoropropionate. Dilute with water, pass through two Sep-Pak plus C18 columns, and the intermediate ethyl fluoropropionate is captured in the Sep-Pak plus C18 columns. Add sodium hydroxide solution to the small column, and the intermediate hydrolysis reacti...

Embodiment 2

[0038] Example 2 R- 18 F-FPA and S- 18 F-FPA biodistribution test in vivo

[0039] 2.1 Biodistribution in vivo

[0040] Determination of R- 18 F-FPA and S- 18 Biodistribution of F-FPA in normal Kunming mice. Forty healthy Kunming mice weighing 20-25 g were randomly divided into 5 groups, with 4 mice at each time point. After intraperitoneal injection of 5% chloral hydrate (6mL / kg) to anesthetize mice, tail vein injection of 0.2mL containing 1.28-2.96MBq (40-80μCi) R- 18 F-FPA or S- 18 F-FPA injection was divided into groups at 5, 30, 60, 90 and 120 minutes after injection, and the mice were sacrificed by cervical dislocation after the eyeballs were removed to collect blood. After dissection, samples of tissues of interest such as brain, heart, lung, liver, spleen, pancreas, kidney, stomach, small intestine, right thigh muscle, and humerus were taken, weighed, and radioactive counts were measured with a gamma counter. All measured data were subtracted from the background...

Embodiment 3

[0043] Example 3 R- 18 F-FPA and S- 18 F-FPA small animal PET / CT imaging test

[0044] 3.1 Small animal PET / CT imaging

[0045] Screening of SPC-A-1 human lung adenocarcinoma model mice, small animal R- 18 F-FPA or S- 18 F-FPA PET-CT imaging. After injecting imaging agent (0.2mL, about 3.7MBq) through the tail vein for 10min, mice were anesthetized by intraperitoneal injection of 5% chloral hydrate (6mL / kg), fixed on a fixed board, and kept warm with a heating pad. After CT scanning, PET data were collected at different time points (30, 60, and 90 min). After attenuation correction, iterative reconstruction obtained cross-sectional, sagittal, coronal tomographic images and PET / CT fusion images. Use software (Inevon Research PET Workplace 4.1) to outline regions of interest (ROIs) such as tumor sites and muscles, and obtain ROIs by measuring the radioactive count and volume of tissue in the region of interest (the default density per gram of tissue is 1g / mL). Percent inje...

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Abstract

The invention relates to 2-<18>F-fluoropropionic acid isomers: R-2-<18>F-fluoropropionic acid (R-<18>F-FPA, formula 1) and S-2-<18>F-fluoropropionic acid (S-18F-FPA, formula 2), a synthesis method and application thereof in preparation of positron emission tomography (PET) imaging agent drugs. Enantiomer R- or S-2-trifluoromethanesulfonic acid-ethyl propionate is adopted as the precursor, and can be obtained by nucleophilic fluorination and hydrolysis two-step reaction. The chiral PET drug radiation synthesis method provided by the invention is simple, has high radiochemical yield, and is convenient for automatic synthesis, and the enantiomers can be used for differential diagnosis and therapeutic effect evaluation of tumors, cardiovascular and cerebrovascular diseases and neuropsychiatric disorders. (formula 1, and formula 2).

Description

[0001] 【Technical field】 [0002] The present invention relates to 2- 18 F-fluoropropionic acid isomer: R-2- 18 F-fluoropropionic acid (R- 18 F-FPA) and S-2- 18 F-fluoropropionic acid (S- 18 F-FPA), its synthesis method and its application in the preparation of positron emission tomography imaging agent medicine. [0003] 【Background technique】 [0004] 11 C-acetate ( 11 C-AC) is a positron emission tomography (PET) imaging agent used to measure heart and brain oxidative metabolism and lipid metabolism in various tumors (such as urinary tract tumors, head and neck cancer, hepatocellular carcinoma, etc.) , the sensitivity of detecting some tumors is higher than 2- 18 F-2-deoxy-D-glucose ( 18 F-FDG)[1]. but 11 C has a short half-life and needs to be provided immediately by the accelerator, and delayed imaging cannot be performed. 18 F-fluoroacetate ( 18 F-FAC) is 11 Analogues of C-AC can compensate for 11 C-AC is insufficient, and has been used in PET imaging studie...

Claims

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Application Information

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IPC IPC(8): C07C53/21C07C51/09A61K51/04A61K101/02
CPCA61K51/0402C07B59/001C07B2200/05C07C51/09C07C53/21C07C67/307C07C69/24
Inventor 唐刚华
Owner GUANGDONG HUIXUAN PHARMA TECH
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