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A method for preparing Stable nuclide labeled acyl carnitine

List of Chinese inventions Patent Application 201911359595.9

SCI paper citation DOI: 10.1002/jlcr.3904

Acylcarnitine is a general term for a large group of small molecule metabolites of fatty acids with different lengths and structures that couple with L-carnitine to form esters. They are produced by carnitine acyltransferase during the catabolism of fatty acids and several Branched-chain amino acid. Because acylcarnitine can pass through mitochondria and cell membranes, it is easily detected in the blood. In fact, recent studies have determined that plasma contains hundreds of acyl carnitines, with fatty acid structures ranging from 2-carbon to 18-carbon, and can contain multiple functional groups, including hydroxyl, carboxyl, and carbon carbon double bonds at different positions.

The concentration of acylcarnitine in the plasma of healthy individuals is relatively stable. However, if one or more enzymes involved in acylcarnitine metabolism produce defects, it may lead to abnormal levels of acylcarnitine, indicating that acylcarnitine analysis is a good indicator for detecting metabolic disorders. Due to the pioneering work of Millington et al., acylcarnitine analysis has become the basis for screening metabolic genetic diseases in newborns. Combined with amino acid analysis, more than 40 rare genetic diseases can be detected simultaneously. For example, the accumulation of octyl carnitine C8 may be a marker of medium chain acyl coenzyme A dehydrogenase deficiency (MCAD), while the increase of short chain propionyl carnitine C3 may indicate the presence of Methylmalonic acid (MMA).

The screening of metabolic genetic diseases in newborns uses tandem mass spectrometry to analyze more than thirty acylcarnitine and ten amino acids extracted from dried blood tablets. In order to quantitatively determine the concentration of these metabolites, it is necessary to provide an internal standard with Stable nuclide labeling of different quality, which is identical to the chemical structure and physical and chemical properties of natural molecules. Because the screening of metabolic genetic diseases in newborns requires the simultaneous determination of over thirty types of acylcarnitine, the quality of the added acylcarnitine internal standard in the analysis cannot interfere with the determination of other natural acylcarnitine. Therefore, selecting appropriate acyl carnitine internal standards is crucial for obtaining accurate analytical results.

We have developed a new method to prepare various Stable nuclide labeled acyl carnitine. By selecting different Stable nuclide, the mass of these acyl carnitines can be increased by any value in the range of 3~12 Da compared with their unlabeled natural molecules. In this way, we can more conveniently select labeled acylcarnitine as an internal standard for mass spectrometry analysis, thereby expanding their clinical application. With this method, we have prepared more than 20 different acyl carnitines, and have the most complete Stable nuclide labeled acyl carnitine product line in the world.