Chronic obstructive pulmonary disease (COPD) is the third leading cause of death and is characterized by clinical symptoms and spirometry. Additional measures for diagnosis can be taken using imaging modalities such as CT. However, the evaluation of lung destruction in COPD is limited by the inability to visualize the activation f pathological processes since imaging modalities are only able to evaluate end-organ damage. In this proposal, we aim to develop molecular imaging probes to target two critical processes in the initiation and progression of COPD. Apoptosis, a process of programmed cellular death, correlates with COPD severity and is not seen in the normal adult lung or in the lungs of smokers without COPD. In the past several years we have demonstrated the successful ability of AxV-128/99mTc to detect apoptosis in vivo in a rabbit smoke exposure emphysema model. Additionally, Phase 1 studies have demonstrated safety of this agent in healthy patients. Therefore, in the first two aims of this proposal we will bring to the clinic AxV-128/99mTc, an Annexin V targeted SPECT/CT imaging probe, to image disease in patients with COPD. In the first Aim we will determine whether the use of AxV-128/99mTc allows the imaging of apoptosis in patients with COPD. In the second Aim we will determine if AxV-128/99mTc SPECT-CT imaging identifies peri-operative lung injury in patients with COPD compared to individuals without COPD. In a third aim, we will develop a new matrix metalloproteinase (MMP) targeted imaging agent. Although apoptosis is an important component of COPD pathogenesis, MMP production is fundamental to the process of lung destruction. Therefore, in this final aim we will perform preclinical studies with an MMP probe in order to detect the presence of MMPs in vivo. It is our hypothesis that the development an MMP probe would complement imaging of apoptosis in a COPD patient population. If successful, such an approach will be a powerful tool to potentially predict disease progression after diagnosis, identify patients at risk for disease exacerbation related lung function decline, and monitor response to disease targeted therapy.
The development of novel imaging methodologies utilizing biologically known pathway targets allows imaging of tissue injury in vivo. Apoptosis and protease production are both implicated in the pathogenesis of COPD and we have demonstrated in a pre- clinical model the efficacy of the AxV-128/Tc probe as a marker of apoptosis. In the present proposal we will validate this agent in patients with COPD and continue this approach by developing a novel MMP-targeted probe for pre-clinical testing.
