In Vivo Cardiovascular Molecular Imaging: Contributions to Precision Medicine and Drug Development

Abstract

Conventional forms of noninvasive cardiovascular imaging that evaluate morphology, function, flow, and metabolism play a vital role in individual treatment decisions, often based on guidelines. Innovations in molecular imaging have enhanced our ability to spatially quantify the expression of a wider array of disease-related proteins, genes, or cell types, or the activity of specific pathogenic pathways. These techniques, which usually rely on design of targeted imaging probes, have already been used extensively in cancer medicine and have now become part of cardiovascular care in conditions such as amyloidosis and sarcoidosis. The recognition that common cardiovascular conditions are caused by a substantial diversity of pathobiologic pathways and the diversity of therapies available for use have rekindled interest in expanding the role of molecular imaging of tissue phenotype to improve precision in diagnosis and therapeutic decision-making. The intent of this article is to raise awareness and understanding of approaches to molecular or cellular imaging of phenotype with targeted probes, and their potential to promote the principles of precision medicine. Also addressed are the diverse roles of molecular imaging to improve precision and efficiency of new drug development at the stages of candidate identification, preclinical testing, and clinical trials.

Keywords: drug discovery; molecular imaging; precision medicine.

Figure 1.

Examples of the diverse roles of in vivo molecular imaging in basic science, preclinical translational science, and patient care.

Figure 2.

Key considerations when designing a molecular imaging approach that influence selection of the biologic target, the imaging probe, and the imaging detector.

Figure 3.. Current status and future opportunities for myocarditis imaging.

Pathogeneses for myocarditis and myocardial inflammation (noncomprehensive list at left) are diverse and include infectious, primary inflammatory, and drug-related causes, each of which varies according to inflammatory cell participants, chemokines/cytokines, and complement activation. Myocarditis imaging currently relies on cardiac magnetic resonance imaging (MRI) with T1, T2, and extracellular volume (ECV) mapping, or positron emission tomography (PET) imaging with nonspecific probes such as fluorodeoxyglucose (FDG), which, in the example shown, can be used to assess response to immunosuppressive therapy. Future opportunities for myocarditis imaging (right) will be provided by novel probes targeted to specific immune cell types, endothelial cell activation markers such as endothelial adhesion molecules, and a broad array of other markers of inflammation, activation, and apoptosis, including cytokines, cytokine receptors, reactive oxygen species (ROS), complement activation, inflammasome (NLRP3) activation, and others. CT indicates computed tomography; DAMP, danger-associated molecular pattern molecule; EGPA, eosinophilic granulomatosis with polyangiitis; HIV, human immunodeficiency virus; ICAM-1, intercellular adhesion molecule-1; MAdCAM-1, mucosal vascular addressin cell adhesion molecule-1; PAN, polyarteritis nodosa; Plt, platelets; PSGL1, p-selectin glycoprotein ligand-1; and VCAM-1, vascular cell adhesion molecule-1. MRI and PET images reproduced and adapted from Lamacie et al and Bohnen et al with permission.

Figure 4.. Molecular imaging of atherosclerosis at various stages of disease development.

A, Detection of very early atherosclerotic changes by contrast-enhanced molecular imaging of endothelial cell adhesion molecules in the rhesus macaque. Left graph shows a rapid increase in carotid artery endothelial ultrasound signal from microbubbles targeted to P-selectin or VCAM-1 after starting Western diet. Images show 2-dimensional B-mode ultrasound and corresponding background-subtracted molecular imaging signal (scale at left) for P-selectin in an animal at 12 months on the diet. Molecular imaging signal for inflammation occurred long before detectable changes of vessel morphology on carotid intima–media thickness (CIMT) imaging (right graph). B, Optical imaging of late-stage plaque inflammation with near-infrared (NIRF) detection of a fluorescent (Cy7) probe targeted to leukocyte mannose receptors. Ex vivo NIRF signal from probe accumulation in plaque in the aorta from an atherosclerotic rabbit model and zoomed comparisons of ex vivo and in vivo images from 1 segment are shown. Cross-sectional histology from 2 segments shows spatial colocalization of targeted probe signal (red) on fluorescent microscopy (FM) with RAM-11 staining for macrophages in the atheroma. (BL = baseline). Adapted with permission from Chadderdon et al and Kim et al (open access CC-BY publication).

Figure 5.. Molecular imaging of mechanisms underlying post–myocardial infarction remodeling.

A, In a murine model of myocardial infarction (MI), molecular imaging signal for a ^99mTc-RP805 (targeted to matrix metalloproteinase-1, -2, -7, -9 -12, and -13) are observed by micro–single-photon emission computed tomography imaging for several weeks within the infarct zone and peri-infarct regions defined by perfusion imaging. Sham-treated control animals had low signal enhancement. B, In patients with recent MI, positron emission tomography molecular imaging with ⁶⁸Ga-pentixafor targeted to C-X-C chemokine receptor type 4 present on a variety of immune cells detects the inflammatory response early after reperfusion therapy, and corresponds spatially with the infarct zone by perfusion imaging with ^99mTc-MIBI. Major adverse cardiac event (MACE) rate was significantly greater for those with higher ⁶⁸Ga-pentixafor activity (determined by receiver operating characteristic curve analysis). HLA indicates horizontal long axis; SA, sort axis; and VLA, vertical long axis. Adapted with permission from Su et al and Werner et al.

Figure 6.. Molecular imaging in drug discovery and drug development.

Potential uses for noninvasive molecular imaging (right italicized notations) are shown for preclinical stages of drug development (beige boxes), clinical testing stages (blue boxes), and postmarketing changes (green box). Estimation of the number of candidate new molecular entities is shown on the left. ADMET indicates absorption, distribution, metabolism, excretion, toxicity; IND, Investigational New Drug application; NDA, New Drug Application; POC, proof-of-concept studies; and POM, proof-of-mechanism studies.