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Abstract：Atherosclerosis-related morbidity and mortality remain a global concern. Atherosclerotic disease follows a slow and silent progression, and the transition from early-stage lesions to vulnerable plaques remains difficult to diagnose. Inflammation is a key component of the development of atherosclerotic plaque and consequent life-threatening complications. This study assessed 111In-DANBIRT as an in vivo, noninvasive SPECT/CT imaging probe targeting an inflammatory marker, Lymphocyte Function Associated Antigen-1 (LFA-1), in atherosclerotic plaques. Methods. Selective binding of 111In-DANBIRT was assessed using Sprague-Dawley rats exposed to filtered air and ozone (1 ppm) by inhalation for 4 hours to induce a circulating leukocytosis and neutrophilia in peripheral blood. After 24 hours, whole blood was collected and incubated with radiolabeled DANBIRT (68Ga-DANBIRT and 111In-DANBIRT). Isolated cell component smeared slides using cytospin technique were stained with Wright-Giemsa stain. Apolipoprotein E-deficient (apoE−/−) mice were fed either a normal diet or a high-fat diet (HFD) for 8 weeks. Longitudinal SPECT/CT imaging was performed 3 hours after administration at baseline, 4, and 8 weeks of HFD diet, followed by tissue harvesting for biodistribution, serum lipid analysis, and histology. 3D autoradiography was performed in both groups 24 hours after administration of 111In-DANBIRT. Results. Increased specific uptake of radiolabeled DANBIRT by neutrophils in the ozone-exposed group was evidenced by the acute immune response due to 4-hour ozone exposure. Molecular imaging performed at 3 hours using SPECT/CT imaging evidenced an exponential longitudinal increase in 111In-DANBIRT uptake in atherosclerosis lesions in HFD-fed mice compared to normal-diet-fed mice. Such results were consistent with increased immune response to vascular injury in cardiovascular and also immune tissues, correlated by 24 hours after administration of 3D autoradiography. Histologic analysis confirmed atherosclerotic disease progression with an increased vascular lesion area in HFD-fed mice compared to normal-diet-fed mice. Conclusion. 111In-DANBIRT is a promising molecular imaging probe to assess inflammation in evolving atheroma and atherosclerotic plaque.
1. Introduction
Atherosclerosis is a chronic cardiovascular disease common in patients exhibiting hypercholesterolemia and other inflammatory risk factors [1]. Prevention and early diagnosis of atherosclerotic disease is a top priority in modern medicine [2], as early lifestyle and medical interventions can slow the rate of atheroma development, potentially averting adverse cardiovascular sequelae. Early diagnosis remains challenging because symptoms become clinically evident at later stages where prevention or reversal of lesions is no longer possible [3]. Inflammation promotes continued vascular remodeling in late stage atheroma, making plaques unstable and vulnerable to rupture or erosion. Pathological plaque rupture is the leading cause of acute coronary syndromes, identified by thrombogenic processes and immune cell infiltration [4]. Histological changes in vulnerable plaques such as thin fibrous cap, intraplaque hemorrhage ,and/or a lipid-rich necrotic core (LRNC) are present in ∼80% of ruptured plaques, but such pathologic features require prolonged and variable time of progression [5]. Cardiovascular inflammation [6] and remodeling due to atherogenic progression [7] have been identified as leading causes of plaque instability [8]. The apoE−/− mouse model fed a high-fat diet (HFD) exhibits rapid development of atheromatous plaques [9], with features and stages that mirror those of human disease [10]. Early stages of atherosclerosis typically include altered homeostasis and activation of vascular endothelium, typified by loss of nitric oxide generation and increased expression of chemokines and adhesion molecules [11], which is evident in the apoE−/− model [12]. T cells and monocytes are recruited to plaques and perivascular regions, but their intraplaque specific roles have only been studied invasively postresection or postmortem imaging [13–15]. Neutrophils, part of the immediate innate response of the immunity, have been identified to have an important role in atherosclerosis development [16, 17] and plaque vulnerability [18]. Accumulation of immune cells has been identified in the early-stage lesion of atheroma where it has been published that enzymes such as matrix metalloproteinase [19, 20] and cathepsins play a major role in the atherosclerosis inflammatory process [21]. Experimental models of ozone exposure are used to recreate acute inflammation in animal experimental models to increase systemic inflammatory chemokines and cellularity [22–24]. DANBIRT (DOTA-butylamino-NorBIRT) (Supplemental Figure 1) was developed by chemical repurposing of BIRT 377, which is a specific therapeutic agent developed for leukemia and lymphoma, as it targets Lymphocyte Function Associated Antigen-1 (LFA-1) on both B and T cells [25–27]. DANBIRT is a small nonionic allosteric inhibitor of LFA-1 [28], an integrin expressed only in leukocytes [25], critical for initiation of a vascular immune response to injury [29, 30]. LFA-1 interacts mostly with the intracellular adhesion molecule-1 (ICAM-1) on endothelial cells to promote leukocyte arrest and transmigration [30]. The interaction between LFA-1/ICAM-1 is mediated by chemokines, and LFA-1 affinity is highly modulated whenever LFA-1 interacts/binds to ICAM-1 [31, 32]. Our laboratory has radiolabeled DANBIRT with various radioisotopes suitable for in vivo SPECT/PET/CT imaging in small animals [33, 34]. 
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