当前位置: X-MOL 学术J Nucl. Med. › 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.)
Pharmacokinetic Assessment of 18F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer
The Journal of Nuclear Medicine ( IF 9.3 ) Pub Date : 2020-03-01 , DOI: 10.2967/jnumed.119.229740
Milan Grkovski , Reema Goel , Simone Krebs , Kevin D. Staton , James J. Harding , Ingo K. Mellinghoff , John L. Humm , Mark P.S. Dunphy

18F-(2S,4R)-4-fluoroglutamine (18F-FGln) is an investigational PET radiotracer for imaging tumor glutamine flux and metabolism. The aim of this study was to investigate its pharmacokinetic properties in patients with cancer. Methods: Fifty lesions from 41 patients (21 men and 20 women, aged 54 ± 14 y) were analyzed. Thirty-minute dynamic PET scans were performed concurrently with a rapid intravenous bolus injection of 232 ± 82 MBq of 18F-FGln, followed by 2 static PET scans at 97 ± 14 and 190 ± 12 min after injection. Five patients also underwent a second 18F-FGln study 4–13 wk after initiation of therapy with glutaminase, dual TORC1/2, or programmed death-1 inhibitors. Blood samples were collected to determine plasma and metabolite fractions and to scale the image-derived input function. Regions of interest were manually drawn to calculate SUVs. Pharmacokinetic modeling with both reversible and irreversible 1- and 2-tissue-compartment models was performed to calculate the kinetic rate constants K1, k2, k3, and k4. The analysis was repeated with truncated 30-min dynamic datasets. Results: Intratumor 18F-FGln uptake patterns demonstrated substantial heterogeneity in different lesion types. In most lesions, the reversible 2-tissue-compartment model was chosen as the most appropriate according to the Akaike information criterion. K1, a surrogate biomarker for 18F-FGln intracellular transport, was the kinetic rate constant that was most correlated both with SUV at 30 min (Spearman ρ = 0.71) and with SUV at 190 min (ρ = 0.51). Only K1 was reproducible from truncated 30-min datasets (intraclass correlation coefficient, 0.96). k3, a surrogate biomarker for glutaminolysis rate, was relatively low in about 50% of lesions. Treatment with glutaminase inhibitor CB-839 substantially reduced the glutaminolysis rates as measured by k3. Conclusion: 18F-FGln dynamic PET is a sensitive tool for studying glutamine transport and metabolism in human malignancies. Analysis of dynamic data facilitates better understanding of 18F-FGln pharmacokinetics and may be necessary for response assessment to targeted therapies that impact intracellular glutamine pool size and tumor glutaminolysis rates.



中文翻译:

18 F-(2 S, 4 R)-4-氟谷氨酰胺在癌症患者中的药代动力学评估

18 F-(2S,4R)-4-氟谷氨酰胺(18 F-FGln)是用于研究肿瘤谷氨酰胺通量和代谢成像的PET示踪剂。这项研究的目的是研究其在癌症患者中的药代动力学特性。方法:对41例患者(21例男性和20例女性,年龄54±14岁)的50个病灶进行了分析。进行30分钟动态PET扫描,同时快速静脉快速推注18 F-FGln 232±82 MBq ,然后在注射后97±14和190±12分钟进行两次静态PET扫描。五名患者也接受了第二次18在开始使用谷氨酰胺酶,双重TORC1 / 2或程序性死亡-1抑制剂治疗后4–13周进行F-FGln研究。收集血样以确定血浆和代谢产物的比例,并缩放图像来源的输入功能。手动绘制了感兴趣的区域以计算SUV。用可逆和不可逆的1-和2-组织室模型进行药代动力学模型,以计算动力学速率常数K 1k 2k 3k 4。使用截断的30分钟动态数据集重复进行分析。结果:肿瘤内18F-FGln摄取模式在不同病变类型中显示出明显的异质性。在大多数病变中,根据Akaike信息标准,选择了可逆的2组织室模型作为最合适的模型。K 118 F-FGln细胞内转运的替代生物标志物,其动力学速率常数与30分钟时的SUV(斯皮尔曼ρ= 0.71)和190分钟时的SUV(ρ= 0.51)最相关。从截短的30分钟数据集中仅可再现K 1(类内相关系数为0.96)。k 3谷氨酰胺分解率的替代生物标志物,约50%的病变相对较低。如用k 3所测量,用谷氨酰胺酶抑制剂CB-839处理实质上降低了谷氨酰胺分解速率。结论: 18 F-FGln动态PET是研究人类恶性肿瘤中谷氨酰胺转运和代谢的灵敏工具。动态数据分析有助于更好地理解18 F-FGln的药代动力学,对于评估影响细胞内谷氨酰胺库大小和肿瘤谷氨酰胺分解率的靶向疗法的反应可能是必要的。

更新日期:2020-03-04
down
wechat
bug