Aarnio Richard, Kirjavainen Anna, Rajander Johan, Forsback Sarita, Kalliokoski Kari, Nuutila Pirjo, Milicevic Zvonko, Coskun Tamer, Haupt Axel, Laitinen Iina, Haaparanta-Solin Merja
MediCity Research Laboratory, University of Turku, Turku, Finland.
Drug Research Doctoral Programme, University of Turku, Turku, Finland.
EJNMMI Res. 2024 Jun 13;14(1):53. doi: 10.1186/s13550-024-01114-5.
Fatty acid uptake can be measured using PET and 14-(R,S)-[F]fluoro-6-thia-heptadecanoic acid ([F]FTHA). However, the relatively rapid rate of [F]FTHA metabolism significantly affects kinetic modeling of tissue uptake. Thus, there is a need for accurate chromatographic methods to analyze the unmetabolized [F]FTHA (parent fraction). Here we present a new radiometabolite analysis (RMA) method, with comparison to a previous method for parent fraction analysis, and its use in a test-retest clinical study under fasting and postprandial conditions. We developed a new thin-layer chromatography (TLC) RMA method for analysis of [F]FTHA parent fraction and its radiometabolites from plasma, by testing stationary phases and eluent combinations. Next, we analyzed [F]FTHA, its radiometabolites, and plasma radioactivity from subjects participating in a clinical study. A total of 17 obese or overweight participants were dosed with [F]FTHA twice under fasting, and twice under postprandial conditions and plasma samples were obtained between 14 min (mean of first sample) and 72 min (mean of last sample) post-injection. Aliquots of 70 plasma samples were analyzed using both methods, enabling head-to-head comparisons. We performed test-retest and group comparisons of the parent fraction and plasma radioactivity.
The new TLC method separated seven [F]FTHA radiometabolite peaks, while the previous method separated three. The new method revealed at least one radiometabolite that was not previously separable from [F]FTHA. From the plasma samples, the mean parent fraction value was on average 7.2 percentage points lower with the new method, compared to the previous method. Repeated [F]FTHA investigations on the same subject revealed reproducible plasma SUV and parent fractions, with different kinetics between the fasted and postprandial conditions.
The newly developed improved radio-TLC method for [F]FTHA RMA enables accurate parent fraction correction, which is required to obtain quantitative data for modelling [F]FTHA PET data. Our test-retest study of fasted and postprandial conditions showed robust reproducibility, and revealed clear differences in the [F]FTHA metabolic rate under different study settings.
EudraCT No: 2020-005211-48, 04Feb2021; and Clinical Trials registry NCT05132335, 29Oct2021, URL: https://classic.
gov/ct2/show/NCT05132335 .
脂肪酸摄取可通过正电子发射断层扫描（PET）和14-(R,S)-[F]氟-6-硫代十七烷酸（[F]FTHA）进行测量。然而，[F]FTHA相对较快的代谢速率显著影响组织摄取的动力学建模。因此，需要准确的色谱方法来分析未代谢的[F]FTHA（母体部分）。在此，我们提出一种新的放射性代谢物分析（RMA）方法，与先前用于母体部分分析的方法进行比较，并展示其在禁食和餐后条件下的重测临床研究中的应用。我们通过测试固定相和洗脱液组合，开发了一种新的薄层色谱（TLC）RMA方法，用于分析血浆中的[F]FTHA母体部分及其放射性代谢物。接下来，我们分析了参与临床研究的受试者的[F]FTHA、其放射性代谢物和血浆放射性。共有17名肥胖或超重参与者在禁食状态下接受两次[F]FTHA给药，在餐后状态下也接受两次给药，并在注射后14分钟（首个样本的平均值）至72分钟（最后一个样本的平均值）之间采集血浆样本。使用两种方法对70份血浆样本的等分试样进行分析，从而进行直接比较。我们对母体部分和血浆放射性进行了重测和组间比较。
新的TLC方法分离出7个[F]FTHA放射性代谢物峰，而先前的方法分离出3个。新方法揭示了至少一种先前无法与[F]FTHA分离的放射性代谢物。从血浆样本来看，与先前方法相比，新方法测得的平均母体部分值平均低7.2个百分点。对同一受试者进行重复的[F]FTHA研究显示，血浆标准化摄取值（SUV）和母体部分具有可重复性，且禁食和餐后条件下的动力学不同。
新开发的用于[F]FTHA RMA的改进型放射性TLC方法能够进行准确的母体部分校正，这是获取用于[F]FTHA PET数据建模的定量数据所必需的。我们在禁食和餐后条件下的重测研究显示出强大的可重复性，并揭示了不同研究环境下[F]FTHA代谢率的明显差异。
欧洲临床试验数据库编号：2020-005211-48，2021年2月4日；以及临床试验注册中心编号NCT05132335，2021年10月29日，网址：https://classic.
gov/ct2/show/NCT05132335 。
