Functional Imaging of Multidrug Resistance with PET

描述(由申请人提供)： 该项目的目标是开发一种用于多药耐药(MDR)功能评估的64Cu(T1/2=12.7h)PET(正电子发射断层扫描)放射性药物，MDR是一种常见的治疗限制现象，在这种现象中，恶性肿瘤对特定类别的药物没有反应或产生抗药性。MDR的特征是P-糖蛋白(Pgp)和多药耐药蛋白(MRP1)浓度升高，从而降低这些药物在耐药细胞中的浓度。 我们的目标是基于这样一个假设，即可以开发出具有亲脂性的阳离子64CuPET放射性药物，其生物学特性等于或优于现有的99m/Tc SPECT(单光子发射计算机断层扫描)放射性药物，这些药物是已知的PGP和MRP1的底物，而且，与SPECT相比，使用PET进行这一过程将提高诊断准确性。该项目的具体目标是：1)确定该放射性药物的最佳化学性质，以及2)其生物学性质的特征。 第一个目标将通过合成一系列亲脂性阳离子二亚胺二肟64Cu配合物的靶向衍生物来实现，我们先前已经证明了该配合物是PGP的底物。这些衍生物的选择将基于现有MDR放射性药物的性质以及我们在该项目过程中开发的结构-功能关系。第二个目标将通过测量耐药和非耐药细胞系对64Cu络合物的摄取、MDR调节剂的效果、血清稳定性和体外非特异性结合来实现。耐药和非耐药肿瘤对复合体的摄取也将在体内进行测量，体内稳定性也将得到测量。这些结构-功能关系将被应用于后续的64Cu络合物的合成。 用于MDR定量功能分析的PET放射性药物的研制成功，将为MDR的实时监测提供有价值的临床工具，有助于化疗方案的优化和MDR逆转剂的评价。

DESCRIPTION (provided by applicant): The objective of this project is the development of a 64Cu (T1/2 = 12.7 h) PET (Positron Emission Tomography) radiopharmaceutical for the functional evaluation of multidrug resistance (MDR), a frequently encountered treatment-limiting phenomenon in which a malignancy fails to respond to or becomes resistant to a specific class of drugs. MDR is characterized by increased concentrations of P-glycoprotein (Pgp) and multidrug-resistance protein (MRP1), which reduce the concentration of these drugs in the resistant cells. Our objective is based on the hypothesis that a lipophilic cationic 64Cu PET radiopharmaceutical can be developed with biological properties that are equal or superior to those of existing 99m/Tc SPECT (Single-Photon Emission Computed Tomography) radiopharmaceuticals that are known to be substrates for Pgp and MRP1, and, furthermore, that the use of PET for this procedure will improve the diagnostic accuracy compared to SPECT. The Specific Aims of this project are: 1) the identification of the optimal chemical properties of this radiopharmaceutical, and 2) the characterization of its biological properties. The first Aim will be accomplished by synthesizing a series of targeted derivatives of the lipophilic cationic diiminedioxime 64Cu complex that we have previously demonstrated is a substrate for Pgp. These derivatives will be chosen based on the properties of existing MDR radiopharmaceuticals as well as the structure-function relationships that we develop in the course of this project. The second Aim will be accomplished by measuring the uptake of the 64Cu complexes in resistant and non-resistant cell lines, the effect of MDR modulators, the serum stability, and the non-specific binding in vitro. The uptake of the complexes by resistant and non-resistant tumors will also be measured in vivo as will the in vivo stability. These structure-function relationships will then be applied to the synthesis of subsequent 64Cu complexes. The successful development of a PET radiopharmaceutical for the quantitative functional assay of MDR will provide a valuable clinical tool for real-time assessment of MDR, which may facilitate optimization of chemotherapy protocols and evaluation of MDR reversal agents.