Novel Strategies to Optimize Targeted Molecular Imaging and Therapy

Improving patients’ clinical outcomes requires many levels of examination, owing to the enormous complexities of human disease and healthcare delivery. Our understanding of disease also requires many different levels of observation. The human experience preconditions us to see the whole person and to relate to them as individuals, each with their own unique set of circumstances. Modern medicine seeks to apply many forms of intervention, including surgical resection, radiation and chemotherapy, and more recently, targeted drug therapy. In this forum, we are concerned with disease and pathophysiology, and how best to reach the site or sites of disease with targeted therapies. Monoclonal antibodies and their fragments have long held promise in targeting epitopes unique to diseased cells, e.g. cancer. Peptides and small molecule ligands that are capable of binding unique expressions of disease are increasingly the focus of drug discovery and development. This thesis focuses on development of radioligands for molecular imaging and therapy and novel strategies to improve their application to achieve greater success. These efforts are pursued in order to improve patient outcomes through more accurate and timely diagnosis, staging, and monitoring of treatment interventions using molecular imaging, and to more effectively treat disease using highly targeted therapies

Imaging of atherosclerosis, targeting LFA-1 on inflammatory cells with 111In-DANBIRT

Background: 111In-DOTA-butylamino-NorBIRT (DANBIRT) is a novel radioligand which binds to Leukocyte Function-associated Antigen-1 (LFA-1), expressed on inflammatory cells. This study evaluated 111In-DANBIRT for the visualization of atherosclerotic plaque inflammation in mice. Methods and Results: ApoE−/− mice, fed an atherogenic diet up to 20 weeks (n = 10), were imaged by SPECT/CT 3 hours post injection of 111In-DANBIRT (~ 200 pmol, ~ 40 MBq). Focal spots of 111In-DANBIRT were visible in the aortic arch of all animals, with an average Target-to-Background Ratio (TBR) of 1.7 ± 0.5. In vivo imaging results were validated by ex vivo SPECT/CT imaging, with a TBR up to 11.5 (range 2.6 to 11.5). Plaques, identified by Oil Red O lipid-staining on excised arteries, co-localized with 111In-DANBIRT uptake as determined by ex vivo autoradiography. Subsequent histological processing and in vitro autoradiography confirmed 111In-DANBIRT uptake at plaque areas containing CD68 expressing macrophages and LFA-1 expressing inflammatory cells. Ex vivo incubation of a human carotid endarterectomy specimen with 111In-DANBIRT (~ 950 nmol, ~ 190 MBq) for 2 hours showed heterogeneous plaque uptake on SPECT/CT, after which immunohistochemical analysis demonstrated co-localization of 111In-DANBIRT uptake and CD68 and LFA-1 expressing cells. Conclusions: Our results indicate the potential of radiolabeled DANBIRT as a relevant imaging radioligand for non-invasive evaluation of atherosclerotic inflammation

Imaging of inflammatory cellular protagonists in human atherosclerosis: a dual-isotope SPECT approach

Purpose: Atherosclerotic plaque development and progression signifies a complex inflammatory disease mediated by a multitude of proinflammatory leukocyte subsets. Using single photon emission computed tomography (SPECT) coupled with computed tomography (CT), this study tested a new dual-isotop