Peptidoglycan-Targeted [18F]3,3,3-Trifluoro-d-alanine Tracer for Imaging Bacterial Infection,JACS Au

当前位置： X-MOL 学术 › JACS Au › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Peptidoglycan-Targeted [18F]3,3,3-Trifluoro-d-alanine Tracer for Imaging Bacterial Infection
JACS Au ( IF 8.5 ) Pub Date : 2024-02-25 , DOI: 10.1021/jacsau.3c00776
Alexandre M Sorlin ₁ , Marina López-Álvarez ₁ , Jacob Biboy ₂ , Joe Gray ₂ , Sarah J Rabbitt ₁ , Junaid Ur Rahim ₁ , Sang Hee Lee ₁ , Kondapa Naidu Bobba ₁ , Joseph Blecha ₁ , Mathew F L Parker _{1,

3} , Robert R Flavell _{1,

4,

5} , Joanne Engel _{6,

7} , Michael Ohliger _{1,

8} , Waldemar Vollmer _{2,

9} , David M Wilson ₁

Affiliation

Department of Radiology, Biomedical Imaging University of California, San Francisco, San Francisco, California 94158, United States.
The Centre for Bacterial Cell Biology, Newcastle University Newcastle, Newcastle upon Tyne NE2 4AX, United Kingdom.
Department of Psychiatry, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York 11794, United States.
UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94158, United States.
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94158, United States.
Department of Medicine, University of California, San Francisco, San Francisco, California 94158, United States.
Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California 94158, United States.
Department of Radiology, Zuckerberg San Francisco General Hospital, San Francisco, California 94110, United States.
Institute for Molecular Bioscience, The University of Queensland, Brisbane 4072, Australia.

Imaging is increasingly used to detect and monitor bacterial infection. Both anatomic (X-rays, computed tomography, ultrasound, and MRI) and nuclear medicine ([¹¹¹In]-WBC SPECT, [¹⁸F]FDG PET) techniques are used in clinical practice but lack specificity for the causative microorganisms themselves. To meet this challenge, many groups have developed imaging methods that target pathogen-specific metabolism, including PET tracers integrated into the bacterial cell wall. We have previously reported the d-amino acid derived PET radiotracers d-methyl-[¹¹C]-methionine, d-[3-¹¹C]-alanine, and d-[3-¹¹C]-alanine-d-alanine, which showed robust bacterial accumulation in vitro and in vivo. Given the clinical importance of radionuclide half-life, in the current study, we developed [¹⁸F]3,3,3-trifluoro-d-alanine (d-[¹⁸F]-CF₃-ala), a fluorine-18 labeled tracer. We tested the hypothesis that d-[¹⁸F]-CF₃-ala would be incorporated into bacterial peptidoglycan given its structural similarity to d-alanine itself. NMR analysis showed that the fluorine-19 parent amino acid d-[¹⁹F]-CF₃-ala was stable in human and mouse serum. d-[¹⁹F]-CF₃-ala was also a poor substrate for d-amino acid oxidase, the enzyme largely responsible for mammalian d-amino acid metabolism and a likely contributor to background signals using d-amino acid derived PET tracers. In addition, d-[¹⁹F]-CF₃-ala showed robust incorporation into Escherichia coli peptidoglycan, as detected by HPLC/mass spectrometry. Based on these promising results, we developed a radiosynthesis of d-[¹⁸F]-CF₃-ala via displacement of a bromo-precursor with [¹⁸F]fluoride followed by chiral stationary phase HPLC. Unexpectedly, the accumulation of d-[¹⁸F]-CF₃-ala by bacteria in vitro was highest for Gram-negative pathogens in particular E. coli. In a murine model of acute bacterial infection, d-[¹⁸F]-CF₃-ala could distinguish live from heat-killed E. coli, with low background signals. These results indicate the viability of [¹⁸F]-modified d-amino acids for infection imaging and indicate that improved specificity for bacterial metabolism can improve tracer performance.

中文翻译：

用于细菌感染成像的肽聚糖靶向 [18F]3,3,3-三氟-d-丙氨酸示踪剂

成像越来越多地用于检测和监测细菌感染。解剖学（X 射线、计算机断层扫描、超声和 MRI）和核医学（[ ¹¹¹ In]-WBC SPECT、[ ¹⁸ F]FDG PET）技术均用于临床实践，但缺乏对致病微生物本身的特异性。为了应对这一挑战，许多研究小组开发了针对病原体特异性代谢的成像方法，包括整合到细菌细胞壁中的 PET 示踪剂。我们之前报道过d-氨基酸衍生的PET放射性示踪剂d-甲基-[ ¹¹ C]-蛋氨酸、 d- [3- ¹¹ C]-丙氨酸和d- [3- ¹¹ C]-丙氨酸-d-丙氨酸，这表明细菌在体外和体内积累强劲。鉴于放射性核素半衰期的临床重要性，在本研究中，我们开发了[ ¹⁸ F]3,3,3-三氟-d-丙氨酸（ d -[ ¹⁸ F]-CF ₃ -ala），一种氟 18标记的示踪剂。我们测试了以下假设：鉴于d -[ ¹⁸ F]-CF ₃ -ala 与d -丙氨酸本身的结构相似，它将被纳入细菌肽聚糖中。 NMR分析表明，氟19母体氨基酸d- [ ¹⁹ F]-CF ₃ -ala在人和小鼠血清中稳定。 d -[ ¹⁹ F]-CF ₃ -ala 也是d - 氨基酸氧化酶的不良底物，该酶主要负责哺乳动物d - 氨基酸代谢，并且可能是使用d - 氨基酸衍生的 PET 示踪剂的背景信号的贡献者。此外，通过HPLC/质谱检测， d- [ ¹⁹ F]-CF ₃ -ala 表现出与大肠杆菌肽聚糖的牢固结合。基于这些有希望的结果，我们通过用[ ¹⁸ F]氟化物置换溴前体，然后进行手性固定相HPLC，开发了d- [ ¹⁸ F]-CF ₃ -ala的放射合成方法。出乎意料的是，体外细菌对d- [ ¹⁸ F]-CF ₃ -ala的积累对于革兰氏阴性病原体，特别是大肠杆菌是最高的。在急性细菌感染的小鼠模型中， d -[ ¹⁸ F]-CF ₃ -ala 可以以低背景信号区分活大肠杆菌和热灭活大肠杆菌。这些结果表明[ ¹⁸ F]-修饰的d-氨基酸用于感染成像的可行性，并表明改善细菌代谢的特异性可以改善示踪剂性能。

更新日期：2024-02-25

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文