The development of radiolabeled probes for imaging and therapy which target the chemokine CXCR4

? DESCRIPTION (provided by applicant): CXCR4 related research has escalated to currently yield a total of 9,201 NCBI publications by March 2015. A total of 3,046 of the 9,201 publications have been cancer related, with 1,586 published within the past 5 years. CXCR4 was first discovered as one of the co-receptors for HIV, and thereafter was found to be expressive in multiple cancers including breast, prostate, lung, colon and multiple myeloma. These malignancies account for 48.8% of all cancers in the USA in 2014, and this does not take into account the many other cancers for which CXCR4 overexpression has not yet been studied. Furthermore, CXCR4 has been identified as having increased expression and importance in higher staged, higher grade, metastatic disease. Non- invasive imaging of overexpressed CXCR4 is an important prognostic tool since the receptor can provide survival and proliferation signals to neoplastic cells. Currently, there is no method to non-invasively evaluate CXCR4 expression within solid tumors. Tests are thus limited to biopsies, which are restricted to a specific site, may give false negative results, and carry with it cost and morbidity. This also assumes that we already the cancer's specific location, such that we can adequately target the biopsy. The development of targeted CXCR4 imaging probes will also open a possibility for the use of CXCR4 directed therapy as a Theranostic model, where probes can be labeled with 18F, 11C and/or 124I radioisotopes for imaging, and with 131I for therapy. The ligands library proposed in this project will be based on high affinity small molecular structures modified for swift radiolabeling. Existing lead compounds with high CXCR4 binding affinities will be modified for radiolabeling without significantly affecting their binding affinity. Complete radiolabeling/purification/formulation procedures will be created to obtain a USP injectable solution that can be replicated for future human studies. Imaging agents will be tested in vivo, and the biodistribution, bioavailability, and pharmacokinetics of the drugs will be determined. The best radio-ligands maybe considered for future human clinical trials. The proposed training plan includes cell biology, organic synthetic chemistry, and small animal imaging training. Several complemental courses will also be included to improve scientific writing skills and other necessary knowledge for the design of radiopharmaceuticals. An image oriented surgery, pathological analysis of recovered specimens, and oncological treatment mentorship is also planned to link all involved fields in cancer management and broaden the trainee's understanding of the individual parts involved. The training fellowship has been design to assure the success of the trainee in his future academic career.