Institute of Nuclear Chemistry, University of Mainz, Mainz, Germany.
Mol Imaging Biol. 2011 Oct;13(5):985-94. doi: 10.1007/s11307-010-0410-1.
The p-glycoprotein (Pgp) is the most prominent member of active drug transporters leading to a multidrug-resistant phenotype. For identification of tumors functionally overexpressing Pgp in vivo, non-invasive imaging techniques are needed.
Six Schiff base compounds were synthesized and labeled with (68)Ge/(68)Ga generator-derived (68)Ga. The compounds were studied in vitro in Pgp-positive tumor cells. The property of being a Pgp substrate was tested by comparison of the tracers uptake in R-3327 Dunning prostate carcinoma AT1 cells in presence and absence of the Pgp-inhibitor verapamil. In vivo investigations were performed with tumor-bearing rats imaged with micro-positron emission tomography.
All ligands were labeled with (68)Ga in yields of >92% beside one (~55%). The tracers showed different accumulation within the cells in vitro (4-60%). In blocking experiments, the ratio (blocked to unblocked) varied from 1.8 to 1.0. For in vivo experiments, (68)Ga-ENBDMPI and (68)Ga-MFL6.MZ were selected. The tumors showed specific uptake of the tracer. Direct intratumoral injection of verapamil increased the tracer concentration by ~25% reflecting the functional Pgp activity.
Two (68)Ga-labeled ligands appear to be valuable for imaging non-invasively the intratumoral Pgp activity. On a long term, patients with multidrug-resistant tumors pre-therapeutically may be identified prior to treatment.
P-糖蛋白（Pgp）是主动药物转运体中最突出的成员，导致多药耐药表型。为了在体内鉴定功能过表达 Pgp 的肿瘤，需要非侵入性成像技术。
合成了 6 种席夫碱化合物，并与（68）Ge/（68）Ga 发生器衍生的（68）Ga 标记。在体外研究了 Pgp 阳性肿瘤细胞中的化合物。通过比较在存在和不存在 Pgp 抑制剂维拉帕米的情况下，R-3327 前列腺癌 AT1 细胞中示踪剂的摄取，测试了作为 Pgp 底物的特性。用荷瘤大鼠进行体内研究，用微正电子发射断层扫描进行成像。
所有配体的标记产率均大于 92%（一个约为 55%）。示踪剂在体外细胞内的积累不同（4-60%）。在阻断实验中，比值（阻断与未阻断）从 1.8 变化到 1.0。对于体内实验，选择了（68）Ga-ENBDMPI 和（68）Ga-MFL6.MZ。肿瘤显示出示踪剂的特异性摄取。直接向肿瘤内注射维拉帕米可使示踪剂浓度增加约 25%，反映了功能性 Pgp 活性。
两种（68）Ga 标记的配体似乎可用于非侵入性成像肿瘤内的 Pgp 活性。从长远来看，在治疗前可以识别出预先具有多药耐药肿瘤的患者。
