采用 PET 测量前列腺肿瘤摄取 16β-18F-氟-5α-二氢睾酮（FDHT）的药代动力学评估。
Pharmacokinetic assessment of the uptake of 16beta-18F-fluoro-5alpha-dihydrotestosterone (FDHT) in prostate tumors as measured by PET.
机构信息
Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
出版信息
J Nucl Med. 2010 Feb;51(2):183-92. doi: 10.2967/jnumed.109.066159. Epub 2010 Jan 15.
UNLABELLED
The aim of this study was to develop a clinically applicable noninvasive method to quantify changes in androgen receptor (AR) levels based on (18)F-16beta-fluoro-5alpha-dihydrotestosterone ((18)F-FDHT) PET in prostate cancer patients undergoing therapy.
METHODS
Thirteen patients underwent dynamic (18)F-FDHT PET over a selected tumor. Concurrent venous blood samples were acquired for blood metabolite analysis. A second cohort of 25 patients injected with (18)F-FDHT underwent dynamic PET of the heart. These data were used to generate a population-based input function, essential for pharmacokinetic modeling. Linear compartmental pharmacokinetic models of increasing complexity were tested on the tumor tissue data. Four suitable models were applied and compared using the Bayesian information criterion (BIC). Model 1 consisted of an instantaneously equilibrating space, followed by a unidirectional trap. Models 2a and 2b contained a reversible space between the instantaneously equilibrating space and the trap, into which metabolites were excluded (2a) or allowed (2b). Model 3 built on model 2b with the addition of a second reversible space preceding the unidirectional trap and from which metabolites were excluded.
RESULTS
The half-life of the (18)F-FDHT in blood was between 6 and 7 min. As a consequence, the uptake of (18)F-FDHT in prostate cancer lesions reached a plateau within 20 min as the blood-borne activity was consumed. Radiolabeled metabolites were shown not to bind to ARs in in vitro studies with CWR22 cells. Model 1 produced reasonable and robust fits for all datasets and was judged best by the BIC for 16 of 26 tumor scans. Models 2a, 2b, and 3 were judged best in 7, 2, and 1 cases, respectively.
CONCLUSION
Our study explores the clinical potential of using (18)F-FDHT PET to estimate free AR concentration. This process involved the estimation of a net uptake parameter such as the k(trap) of model 1 that could serve as a surrogate measure of AR expression in metastatic prostate cancer. Our initial studies suggest that a simple body mass-normalized standardized uptake value correlates reasonably well to model-based k(trap) estimates, which we surmise may be proportional to AR expression. Validation studies to test this hypothesis are underway.
目的
本研究旨在开发一种临床可行的非侵入性方法，基于前列腺癌患者治疗过程中的（18）F-16β-氟-5α-二氢睾酮（（18）F-FDHT）PET，定量检测雄激素受体（AR）水平的变化。
方法
13 例患者在选定的肿瘤部位进行动态（18）F-FDHT PET，同时采集静脉血样进行血液代谢物分析。第二组 25 例患者注射（18）F-FDHT 后，对心脏进行动态 PET。这些数据用于生成群体基础输入函数，这对于药代动力学建模是必不可少的。在肿瘤组织数据上测试了越来越复杂的线性房室药代动力学模型。应用四种合适的模型，并使用贝叶斯信息准则（BIC）进行比较。模型 1 由一个瞬时平衡空间组成，后面跟着一个单向陷井。模型 2a 和 2b 在瞬时平衡空间和陷井之间包含一个可反向的空间，代谢物被排除（2a）或允许进入（2b）。模型 3 基于模型 2b，在单向陷井前增加了第二个可反向的空间，代谢物被排除。
结果
（18）F-FDHT 在血液中的半衰期为 6-7 分钟。因此，由于血液中放射性标记物的活性被消耗，前列腺癌病灶中（18）F-FDHT 的摄取在 20 分钟内达到平台期。在与 CWR22 细胞的体外研究中，已证明放射性标记的代谢物不会与 AR 结合。对于 26 例肿瘤扫描中的 16 例，模型 1 产生了合理而稳健的拟合，而根据 BIC，模型 2a、2b 和 3 分别是最佳的。
结论
我们的研究探索了使用（18）F-FDHT PET 来估计游离 AR 浓度的临床潜力。该过程涉及估计净摄取参数，如模型 1 的 k（陷井），该参数可用作转移性前列腺癌中 AR 表达的替代测量。我们的初步研究表明，一个简单的体质量归一化标准化摄取值与基于模型的 k（陷井）估计值相当相关，我们推测这可能与 AR 表达成正比。正在进行验证研究来检验这一假设。
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