Lymphoma-Specific Ligands; Pharmacokinetics, Radioimaging and Therapeutics

该计划的总体目标是放射性同位素靶向分子和策略的转化发展，以实现PET更特异性和更敏感的检测，并提供增强的全身放射治疗癌症。程序3是中心的发展和翻译这些分子通过体内评价选定的肽模拟物作为低聚物，成像或治疗剂。程序3将(1)制备所选的dota -拟肽低聚物作为放射性偶联物；(2)保证体外用药质量；(3)在小鼠和狗身上进行体内小鼠药代动力学和微pet成像研究，以及(4)在这些动物身上进行选定的治疗研究。这些关键问题将以系统的方式加以处理。如有需要，将制定进一步的战略来实现这一方案的总体目标。已经确定了五个具体目标。1)最初将仔细选择两种分子格式用于放射性标记的拟肽，#1提供一种有效的

The overall goal of this program is the translational development of radioisotope targeting molecules and strategies to achieve more specific and sensitive detection with PET and delivery of enhanced systemic radiotherapy to cancer. Program 3 is central to the development and the translation of these molecules by in vivo evaluation of selected peptidomimetics as oligomers, to imaging or therapeutic agents. Program 3 will (1) prepare the selected DOTA-peptidomimetic oligomers as radioconjugates; (2) assure in vitro pharmaceutical quality; (3) perform in vivo mouse pharmacokinetic and microPET imaging studies in mice and dogs, as well as (4) perform selected therapeutic studies in these animals. These key issues will be addressed in a systematic approach. If needed further strategies will be developed to achieve the overall goal of this program. Five specific aims have been delineated. 1) The initial careful selection of 2 molecular formats for radiolabeled peptidomimetic will be made, #1 providing an effective target to normal tissue ratio (T/NT) for imaging and #2, an effective therapeutic index (Tl) for radionuclide therapy. These 2 oligomeric formats will be chosen from oligomers in several multimeric forms using in vivo pharmacokinetics and PET/CT imaging in mice. 2) The peptidomimetics will be selected by study in these oligomeric forms, and determination of those, which have the best potential for effective PET imaging and/or systemic radionuclide radiotherapy. This determination wil be made by quantitative in vivo pharmacokinetic studies and dosimetry calculations of the various peptidomimetic oligomers as radioconjugates using microPET/CT and biodistribution studies in nude mice bearing lymphoma xenografts, and PET/CT studies in dogs having spontaneous canine lymphoma. 3) Selected peptidomimetic as radioconjugate oligomers will be evaluated in therapy protocols in mice bearing human xenograft models and the MTD and efficacy will be compared to calculated dosimetry. 4) 64Cu peptidomimetic oligomers will be evaluated for their ability to provide the in vivo targeting signal leading to sensitive tumor detection by PET imaging of micrometastases in larger animals (dogs) with spontaneous lymphoma. Further study of the pharmacokinetics of these agents in PET quantitative imaging Canine protocols will be used to determine the Tl and calculated dosimetry for selected peptidomimetic oligomers, so as to predict and perform safe 90Y-peptidomimetic oligomer MTD therapy in these animals. 5) Selection will be made of a 64Cu and/or 111ln/90Y-peptidomimetic oligomer(s) with characteristics likely to substantially enhance T/NT and /or Tl over current lymphoma agents, for future human protocol trials. Preliminary microPET imaging in mice has demonstrated obvious tumor targeting of an initial 64Cu peptidomimetic. This Program is considered to have a high likelihood of success.