Biological Evaluation of d-[¹⁸F]Fluoroalanine and d-[¹⁸F]Fluoroalanine-d₃ as Positron Emission Tomography Imaging Tracers for Bacterial Infection.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-08-22 Epub Date: 2024-07-31 DOI:10.1021/acs.jmedchem.4c00783

Kaixuan Li, Jinnette Tolentino Collado, Jocelyn A Marden, Alyssa C Pollard, Shuwen Guo, Peter J Tonge, Wenchao Qu

{"title":"Biological Evaluation of d-[18F]Fluoroalanine and d-[18F]Fluoroalanine-d3 as Positron Emission Tomography Imaging Tracers for Bacterial Infection.","authors":"Kaixuan Li, Jinnette Tolentino Collado, Jocelyn A Marden, Alyssa C Pollard, Shuwen Guo, Peter J Tonge, Wenchao Qu","doi":"10.1021/acs.jmedchem.4c00783","DOIUrl":null,"url":null,"abstract":"d-Amino acids such as d-alanine are substrates for bacterial peptidoglycan biosynthesis and are selectively taken up by bacteria and not mammalian cells. Consequently, d-amino acid metabolism is an attractive target for antibiotic discovery and the development of bacteria-specific imaging agents. d-Fluoroalanine and the deuterium-labeled analogue fludalanine (MK641) were originally explored as antibiotics by Merck but failed in clinical trials due to unaccepted toxicity. Herein, we synthesized a fluorine-18 labeled d-fluoroalanine, d-3-[18F]fluoroalanine (d-[18F]FAla), and its deuterated analogue, d-3-[18F]fluoroalanine-d3 (d-[18F]FAla-d3), and evaluated their capability to image bacterial infection. Both d-[18F]FAla and d-[18F]FAla-d3 can accumulate up to 0.64-0.78% ID/cc in the infectious area at 15 min postinjection. Despite the reduction of in vivo defluorination not being observed for deuterated 18F-labeled d-fluoroalanine, these radiolabeled d-alanine analogues were able to differentiate bacterial infection from sterile inflammation in a soft-tissue model of S. aureus infection.","PeriodicalId":46,"journal":{"name":"Journal of Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":6.8000,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11342404/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1021/acs.jmedchem.4c00783","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/31 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}

引用次数: 0

Abstract

d-Amino acids such as d-alanine are substrates for bacterial peptidoglycan biosynthesis and are selectively taken up by bacteria and not mammalian cells. Consequently, d-amino acid metabolism is an attractive target for antibiotic discovery and the development of bacteria-specific imaging agents. d-Fluoroalanine and the deuterium-labeled analogue fludalanine (MK641) were originally explored as antibiotics by Merck but failed in clinical trials due to unaccepted toxicity. Herein, we synthesized a fluorine-18 labeled d-fluoroalanine, d-3-[¹⁸F]fluoroalanine (d-[¹⁸F]FAla), and its deuterated analogue, d-3-[¹⁸F]fluoroalanine-d₃ (d-[¹⁸F]FAla-d₃), and evaluated their capability to image bacterial infection. Both d-[¹⁸F]FAla and d-[¹⁸F]FAla-d₃ can accumulate up to 0.64-0.78% ID/cc in the infectious area at 15 min postinjection. Despite the reduction of in vivo defluorination not being observed for deuterated ¹⁸F-labeled d-fluoroalanine, these radiolabeled d-alanine analogues were able to differentiate bacterial infection from sterile inflammation in a soft-tissue model of S. aureus infection.

Abstract Image

查看原文本刊更多论文

d-[18F]Fluoroalanine 和 d-[18F]Fluoroalanine-d3 作为细菌感染正电子发射断层成像示踪剂的生物学评估

d-氨基酸（如 d-丙氨酸）是细菌肽聚糖生物合成的底物，可被细菌而非哺乳动物细胞选择性吸收。因此，d-氨基酸代谢是抗生素发现和细菌特异性成像剂开发的一个有吸引力的目标。d-氟丙氨酸和氘标记的类似物氟达丙氨酸（MK641）最初被默克公司开发为抗生素，但由于毒性无法接受而在临床试验中失败。在此，我们合成了氟-18 标记的 d-氟丙氨酸、d-3-[18F]氟丙氨酸（d-[18F]FAla）及其氘化类似物 d-3-[18F]氟丙氨酸-d3（d-[18F]FAla-d3），并评估了它们对细菌感染的成像能力。注射后15分钟，d-[18F]FAla和d-[18F]FAla-d3都能在感染区域积聚高达0.64-0.78% ID/cc。尽管氚化 18F 标记的 d-氟丙氨酸没有观察到体内脱氟的减少，但这些放射性标记的 d-丙氨酸类似物能够在金黄色葡萄球菌感染的软组织模型中区分细菌感染和无菌炎症。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.