GRPR/PSMA Targeting Agents for Prostate Cancer Diagnosis

据美国癌症协会估计，前列腺癌将占180，890个新病例 2016年有26，120人死亡，仍然是最常见的癌症和第二大原因 在美国男性癌症死亡率中。本研究应用为设计提供理论依据 并开发基于两种经过充分验证的生物标志物的新诊断剂，用于早期和晚期 前列腺癌的检测，是核心的研究使命的美国国务院 退伍军人事务部寻求基本知识，以增强健康，延长寿命，减少疾病， 美国退伍军人的残疾。 本研究应用的主要目的是开发一种代谢稳定的二价（双重受体 胃泌素释放肽受体/前列腺特异性膜抗原（GRPR/PSMA）靶向 用于GRPR和PSMA的单光子发射计算机断层扫描（SPECT）成像的放射性配体 前列腺肿瘤阳性GRPR和PSMA是经过充分验证的前列腺癌生物标志物， 在大多数前列腺癌的表面上大量表达。因为前列腺癌细胞 似乎差异表达特异性受体，这取决于可能包括慢性和 由于具有转移性，因此逻辑上可以得出，能够靶向多于一种生物标志物的化合物将 具有与前列腺癌的早期和慢性/转移阶段结合的潜力， 对疾病的两个阶段进行及时和准确的诊断。 该申请包含四个独立且明确界定的具体目标： 1.新的二价GRPR/PSMA靶向放射性配体的合成、纯化和表征。 2.为了验证GRPR/PSMA靶向探针在体外GRPR/PSMA中的细胞靶向能力， 表达细胞。 3.评价靶向药物的药代动力学、药理学、稳定性和SPECT成像潜力 GRPR/PSMA表达的前列腺肿瘤中的探针。 4.定量药代动力学肿瘤建模和最可行的单剂量急性毒性研究 分子影像学候选人

According to the American Cancer Society, prostate cancer will account for an estimated 180,890 new cases and 26,120 deaths in 2016, continuing to be the most commonly diagnosed cancer and second-leading cause of cancer death in men in the United States. This research application provides rationale toward the design and development of new diagnostic agents based upon two well-validated biomarkers for early and late-stage detection of prostate cancer and is central to the research mission of the United States Department of Veterans' Affairs of seeking fundamental knowledge to enhance health, lengthen life, and reduce illness and disability of American veterans. The primary objective of this research application is to develop a metabolically stable, bivalent (dual receptor targeting), gastrin releasing peptide receptor/prostate-specific membrane antigen (GRPR/PSMA) targeting radioligand for Single Photon Emission Computed Tomography (SPECT) imaging of GRPR- and PSMA- positive prostate tumors. The GRPR and PSMA are well-validated prostate cancer biomarkers that are expressed in very high numbers on the surfaces of most prostate cancers. Because prostate cancer cells seem to differentially express specific receptors depending upon factors that may include chronicity and metastatic nature, it logically follows that a compound capable of targeting more than one biomarker would have the potential of binding to both early and chronic/metastatic stages of prostate cancer, enabling a more prompt and accurate diagnostic profile for both stages of disease. This application contains four discrete and well-delineated specific objectives: 1. Synthesis, purification, and characterization of new bivalent GRPR/PSMA-targeting radioligands. 2. To validate the cell targeting capacity of the GRPR/PSMA-targeting probes in vitro in GRPR/PSMA- expressing cells. 3. To evaluate the pharmacokinetics, pharmacology, stability, and SPECT imaging potential of the targeting probes in GRPR/PSMA-expressing prostate tumors in mice. 4. Quantitative pharmacokinetic tumor modeling and single dose acute toxicity study of the most viable molecular imaging candidate.