Brooks Allen F, Witek Jason A, Winton Wade P, Stauff Jenelle, Henderson Bradford, Scott Peter J H, Viglianti Benjamin L
Division of Nuclear Medicine, Department of Radiology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, United States.
The Interdepartmental Program in Medicinal Chemistry, The University of Michigan, Ann Arbor, Michigan 48109, United States.
ACS Med Chem Lett. 2024 Apr 19;15(8):1227-1231. doi: 10.1021/acsmedchemlett.4c00074. eCollection 2024 Aug 8.
Cholesteryl ester analogues of [F]FNP-59 have the ability to provide information on cholesterol trafficking and utilization at earlier time points than those of [F]FNP-59 or [I]NP-59. It is well-known that free cholesterol and cholesteryl esters have differing distribution profiles and that they can be interconverted enzymatically. Substitution of the ester influences the rate of cholesterol ester hydrolysis and the subsequent mixing of cholesterol esters with the lipid pool in the body. This can be utilized by preparing esters that are more readily taken up by lipoprotein, are quickly hydrolyzed and mixed with the endogenous lipid pool and delivered to tissues of interest more quickly than free cholesterol analogues that require esterification for lipoprotein association. The acetyl ester of FNP-59 demonstrated the preferred uptake properties and response to adrenal cortical manipulation, indicating its ability to image hormone production. Finally, dosimetry studies were conducted in preparation for the clinical translation of [F]3AcFNP-59.
[F]FNP-59的胆固醇酯类似物能够比[F]FNP-59或[I]NP-59在更早的时间点提供有关胆固醇转运和利用的信息。众所周知，游离胆固醇和胆固醇酯具有不同的分布特征，并且它们可以通过酶促作用相互转化。酯的取代会影响胆固醇酯水解的速率以及随后胆固醇酯与体内脂质池的混合。这可以通过制备更容易被脂蛋白摄取、快速水解并与内源性脂质池混合，且比需要酯化才能与脂蛋白结合的游离胆固醇类似物更快地输送到感兴趣组织的酯来实现。FNP-59的乙酰酯表现出优先摄取特性和对肾上腺皮质操作的反应，表明其具有对激素产生进行成像的能力。最后，进行了剂量学研究，为[F]3AcFNP-59的临床转化做准备。
