PET Tracer for Imaging of Lung Inflammation

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Abstract. Lung transplantation is a well-established surgical intervention in advanced stages of the disease in pulmonary medicine. Despite improvements in surgical procedures and immunosuppressive therapeutic paradigms, the median survival rate continues to be 6 years. Literature precedents show that chronic lung allograft dysfunction (CLAD) is the most significant barrier to long-term survival of lung transplantation. However, prediction and early diagnosis of CLAD using current techniques continues to be problematic due to lower sensitivity (HRCT) and specificity (circulating biomarkers). Currently, the reference standard to detect acute rejection is a histopathological grading of transbronchial biopsies (TBBs), however, it is an invasive technique with several limitations (bleeding, inconsistent outcomes, inherent risks associated with repetitive procedures) including detection at advanced stages of the disease. Therefore, agents capable of offering non-invasive assessment of chronic rejection after transplantation are a highly desirable diagnostic nuclear medicine resource, yet continues to be an unmet need. To accomplish this objective, we have developed a new PET tracer (named as 68Ga-Galuminox), which offers noninvasive assessment of acute lung injury, and also demonstrates promising higher uptake in alveolar macrophages of mouse ex vivo lung transplant model of CLAD, and human lung recipients with a CLAD diagnosis compared to CLAD free subjects. Finally, preliminary 68Ga-Galuminox preclinical PET imaging in our mouse CLAD model has revealed (at 30 min post tail-vein injection) 2-fold higher retention in the left transplanted lung with early signs of CLAD when compared to the non-diseased (untransplanted) right lung. Notably, these observations are also consistent with the observed activation of macrophages and PMNs in CLAD lungs as measured by flow cytometry that identifies single cell Galuminox uptake by detecting its native fluorescence. Armed with this supporting information, aims of our preclinical translational RO1 are: Aim 1: Aim 1: Perform radiation dosimetry to determine human effective dose equivalent (HED), toxicology studies, and GMP validation runs for Galuminox to prepare for an IND filing; Aim 2: Perform first-in-human studies using 68Ga-Galuminox: evaluate dosimetry, biodistribution, safety, and imaging characteristics following a single injection at rest (n=8, 4 males; 4 females); and Aim 3: To evaluate performance of 68Ga-Galuminox and 18F-FDG for detection of CLAD pathogenesis in a mouse model of lung transplantation; Aim 3.1: To determine if 68Ga-Galuminox can detect early and late CLAD pathogenesis; Aim 3.2: To determine if 68Ga- Galuminox can be used to evaluate responses to CLAD treatment; and Aim 3.3: Biochemically characterize mechanism(s) of location of the 68Ga-Galuminox through cell accumulation, sub-cellular fractionation studies, pharmacokinetics, and LPS-induced inflammation either in presence or absence of mitoTempo (MTT) and Dexrazoxane (DEX) in rodents to assess its ability to serve as noninvasive molecular imaging agent for monitoring lung injury. Successful accomplishment of proposed aims could enable: a) deployment of a noninvasive redox-sensitive reporter probe as a diagnostic tool for stratification of patients with a risk factor for CLAD; b) potentially new interventional opportunities; c) enabling longitudinal studies of disease pathology; and d) monitoring therapeutic efficacy of drugs. Combined factors could significantly advance management of CLAD patients with potential detection of CLAD at earliest stages.