Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
Nucl Med Biol. 2011 Apr;38(3):301-12. doi: 10.1016/j.nucmedbio.2010.10.004. Epub 2010 Dec 3.
L-amino acid-based tracers have established their important role as tumor metabolic imaging agents. Recently, a number of studies demonstrated that D-amino acids may have improved imaging properties than their corresponding L-isomers. We synthesized and evaluated the D-isomer of a new phenylalanine derivative, p-(2-[(18)F]fluoroethyl)-phenylalanine ([(18)F]FEP), in comparison to its L-isomer and previously reported the L- and D-isomers of O-(2-[(18)F]fluoroethyl)-tyrosine ([(18)F]FET).
L- and D-Isomers of [(18)F]FET and [(18)F]FEP were successfully synthesized via a rapid and efficient two-step nucleophilic fluorination and deprotection reaction. In vitro studies were carried out in 9L glioma cells. In in vivo studies, Fisher 344 rats bearing the 9L tumor model were used.
L- and D-Isomers of (18)F-fluoroalkyl tyrosine and phenylalanine derivatives were efficiently labeled with high enantiomeric purity (>95%), good yield (11-45%) and high specific activity (21-75 GBq/μmol). D-[(18)F]FEP showed a similar linear time-dependent uptake as D-[(18)F]FET, while their corresponding L-isomers had much faster and higher uptake (4.3- to 16.0-fold at maximum uptake). The maximum uptake of the new compounds, L- and D-[(18)F]FEP, was 1.4- and 5.2-fold of that reported for L- and D-[(18)F]FET, respectively. Transport characterization studies indicated that both L- and D-[(18)F]FEP were selective substrates for system L. While L-[(18)F]FEP exhibited preference towards one subtype of system L, LAT1, D-[(18)F]FEP did not exhibit the same preference. Small animal PET imaging studies showed that both L- and D-[(18)F]FEP had higher uptake in 9L tumor compared to surrounding tissues, but D-isomer had lower tumor-to-muscle ratio in comparison with its L-isomer.
Both L- and D-[(18)F]FEP are substrates for system L amino acid transporter with different preference toward its subtypes. Small animal imaging studies of 9L tumor showed that D-[(18)F]FEP did not show better imaging properties than their corresponding L-isomer.
L-氨基酸基示踪剂已作为肿瘤代谢成像剂确立了其重要地位。最近，许多研究表明，D-氨基酸可能具有比相应的 L-异构体更好的成像特性。我们合成并评估了一种新苯丙氨酸衍生物的 D-异构体，对-(2-[(18)F]氟乙基)-苯丙氨酸([(18)F]FEP)，并与 L-异构体和之前报道的 O-(2-[(18)F]氟乙基)-酪氨酸([(18)F]FET)的 L-和 D-异构体进行了比较。
通过快速高效的两步亲核氟化和脱保护反应，成功合成了[(18)F]FET 和 [(18)F]FEP 的 L-和 D-异构体。在 9L 神经胶质瘤细胞中进行了体外研究。在体内研究中，使用携带 9L 肿瘤模型的 Fisher 344 大鼠。
L-和 D-异构体的(18)F-氟烷基酪氨酸和苯丙氨酸衍生物均以高对映体纯度(>95%)、良好的产率(11-45%)和高比活度(21-75GBq/μmol)进行了高效标记。D-[(18)F]FEP 的摄取呈类似的线性时依赖性，而其相应的 L-异构体的摄取更快、更高(最大摄取时的 4.3-16.0 倍)。新化合物 L-和 D-[(18)F]FEP 的最大摄取量分别是 L-和 D-[(18)F]FET 的 1.4-和 5.2 倍。转运特性研究表明，L-和 D-[(18)F]FEP 均为系统 L 的选择性底物。虽然 L-[(18)F]FEP 对系统 L 的一种亚型 LAT1 表现出偏好，但 D-[(18)F]FEP 没有表现出相同的偏好。小动物 PET 成像研究表明，与周围组织相比，L-和 D-[(18)F]FEP 在 9L 肿瘤中的摄取均较高，但与 L-异构体相比，D-异构体的肿瘤与肌肉比值较低。
L-和 D-[(18)F]FEP 均为系统 L 氨基酸转运蛋白的底物，对其亚型具有不同的偏好。9L 肿瘤的小动物成像研究表明，D-[(18)F]FEP 并没有比相应的 L-异构体表现出更好的成像特性。
