Department of Biochemistry and Structural Biology , Weill Cornell Graduate School , New York , New York 10065 , United States.
Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program , New York , New York 10065 , United States.
ACS Chem Biol. 2019 Apr 19;14(4):665-673. doi: 10.1021/acschembio.8b01044. Epub 2019 Mar 27.
Alterations in arginase enzyme expression are linked with various diseases and have been shown to support disease progression, thus motivating the development of an imaging probe for this enzymatic target. C-enriched arginine can be used as a hyperpolarized (HP) magnetic resonance (MR) probe for arginase flux since the arginine carbon-6 resonance (157 ppm) is converted to urea (163 ppm) following arginase-catalyzed hydrolysis. However, scalar relaxation from adjacent N-nuclei shortens cabon-6 T and T times, yielding poor spectral properties. To address these limitations, we report the synthesis of [6-C,N]-arginine and demonstrate that N-enrichment increases carbon-6 relaxation times, thereby improving signal-to-noise ratio and spectral resolution. By overcoming these limitations with this novel isotope-labeling scheme, we were able to perform in vitro and in vivo arginase activity measurements with HP MR. We present HP [6-C,N]-arginine as a noninvasive arginase imaging agent for preclinical studies, with the potential for future clinical diagnostic use.
精氨酸酶表达的改变与各种疾病有关，并已被证明支持疾病的进展，因此激发了针对这种酶靶标的成像探针的开发。由于精氨酸的碳-6 共振（157 ppm）在精氨酸酶催化水解后转化为尿素（163 ppm），因此富含 C 的精氨酸可用作超极化（HP）磁共振（MR）探针来检测精氨酸酶的通量。然而，来自相邻 N-核的标量弛豫缩短了碳-6 的 T 1 和 T 2 弛豫时间，导致光谱性质较差。为了解决这些限制，我们报告了 [6-C,N]-精氨酸的合成，并证明 N 富集增加了碳-6 的弛豫时间，从而提高了信噪比和光谱分辨率。通过使用这种新的同位素标记方案克服这些限制，我们能够使用 HP-MR 进行体外和体内精氨酸酶活性测量。我们提出了 HP [6-C,N]-精氨酸作为一种用于临床前研究的非侵入性精氨酸酶成像剂，具有未来临床诊断用途的潜力。
