In vivo near-infrared fluorescent optical imaging for CNS drug discovery

ABSTRACT

Introduction

In vivo imaging technologies have become integral and essential component of drug discovery, development, and clinical assessment for central nervous system (CNS) diseases. Near-infrared (NIR) fluorescence imaging in the range of 650–950 nm is widely used for pre-clinical in vivo imaging studies. The recent expansion of NIR imaging into the shortwave infrared (SWIR, 1000–1700 nm) window enabled improvements in tissue penetration and resolution required for anatomical, dynamic, and molecular neuroimaging with high potential for clinical translation.

Areas covered

This review focuses on the latest progress in near-infrared (NIR)-fluorescent optical imaging modalities with an emphasis on the SWIR window. Advantages and challenges in developing novel organic and inorganic SWIR emitters, with special attention to their toxicology and pharmacology, are discussed. Examples of their application in preclinical imaging of brain function and pathology provide a platform to assess the potential for their clinical translation.

Expert opinion

Propelled through concomitant technological advancements in imaging instrumentation, algorithms and new SWIR emitters, SWIR imaging has addressed key barriers to optical imaging modalities used in pre-clinical studies addressing the CNS. Development of biocompatible SWIR emitters and adoption of SWIR into multi-modal imaging modalities promise to rapidly advance optical imaging into translational studies and clinical applications.

KEYWORDS:

• Fluorescent optical imaging
• near infrared
• shortwave infrared
• indocyanine green
• quantum dots
• single wall carbon nanotubes
• central nervous system
• indium gallium arsenide (InGaAs) camera
• brain vasculature
• brain cancer

Article highlights

• Optical imaging modalities provide access to critical biodistribution, PK/PD, and molecular information to de-risk drug discovery and preclinical development.

• Optical imaging in the shortwave infrared (SWIR) spectral window achieves higher tissue transparency, resolution, and depth penetration than in the near infrared-I (NIR-I) window.

• The SWIR region can be divided into two sub-windows, the NIR-IIa (1.3–1.4 μm) and NIR-IIb (1.5–1.7 μm), both with improved imaging metrics.

• SWIR enables a dynamic, longitudinal, quantitative, noninvasive imaging of organs and tissues not accessible in other optical wavelengths such as the brain and deep brain vasculature trough the intact skull.

• Small organic fluorophores are the imaging probes of choice for in vivo imaging due to their high biocompatibility, favorable pharmacokinetics, and clinical translatability (e.g., ICG, and methylene blue). However, their emission in the SWIR region has been limited by the low quantum yield (QY) and poor photostability in water.

• Inorganic nanoparticles such as single-wall carbon nanotubes (SWCNTs) and quantum dots (QDs) exhibit excellent characteristics for imaging applications due to their higher fluorescence QY, photostability, and tunable emission wavelengths. However, their potential toxicity remains the main limitation for clinical translation.

• The field of optical imaging is rapidly advancing instrumentation, detectors, algorithms, and probe development to achieve transparency and resolution for preclinical in vivo imaging comparable to that achieved by radioactive isotope-dependent PET and SPECT modalities.

Acknowledgments

The authors would like to acknowledge Dr. Umar Iqbal, Ms. Dongling Zhang, and Dr. Robert Monette for their contribution to the imaging of the mice presented in this review using the IR VIVO (Photon etc., QC, Canada) and IMA IR microscope (Photon etc., QC, Canada) and to Mr. Mario Mercier and Ms. Jaqueline Slinn for the animal handling and intravenous injections of contrast agents during the imaging sessions. Experiments were approved by the National Research Council Canada (NRCC) Animal Care Committee in accordance with Canadian Council on Animal Care guidelines.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.