In the field of medical imaging science, the concept of multimodality is providing the driving force for the development of the next generation of imaging techniques. The latest hybrid systems such as PET/CT and PET/MRI are transforming the clinical management of cancer patients by consolidating the noninvasive localization and temporal quantification of changes in tissue function and physiology available from PET, with the high-resolution anatomic maps provided by CT or MRI (1
In contrast to the immediate clinical impact of nuclear tomographic imaging, optical methods such fluorescence-mediated tomography and bioluminescence imaging have been largely restricted to use in preclinical models. Reasons for the limited clinical translation of optical modalities lie in the inherent limitations imposed by high rates of scattering and poor tissue penetration at the human scale. Each of these limitations leads to increased difficulty in providing the quantitative analysis of data required for practical applications in the clinic. As a consequence of these in vivo limitations, recent advances in the field of optical imaging have focused on developing methods for imaging microscopic events at the cellular and molecular level.
Endoscopy and surgery could benefit from the translation of optical imaging techniques to visualize tumor lesions or metastatic involvement intraoperatively and thereby provide real-time information to guide surgical resection (3
). However, at present there are no clinically approved targeted probes for use with targeted fluorescence-reflectance imaging or fluorescence-mediated tomography. Further technical and theoretic challenges mean that to date, the research into developing hybrid systems that combine nuclear and anatomic methods with optical imaging cameras is limited (1
). Currently intraoperative methods to detect radionuclides are limited by the use of hand-held probes that do not provide any spatial information, whereas pure optical approaches are limited by the lack of clinically approved targeted agents. Because 2-dimensional imaging would require large, expensive, and bulky equipment unsuitable for an operating suite, no method is currently available to use the multiplicity of approved radiotracers in the clinic.
The emission of a continuum of ultraviolet and visible light from the decay of certain radionuclides in the condensed phase (now known as the Cerenkov effect) was first observed in 1926 and was characterized by Pavel A. Cerenkov in 1934 (5
). Later, in 1958—and along with his colleagues Ilya Frank and Igor Tamm—Cerenkov was awarded the Nobel Prize in Physics, “for the discovery and the interpretation of the Cerenkov effect.” Cerenkov radiation arises when charged particles, such as a β- (β−
) or an α-particle, travel through an optically transparent, insulating material with a velocity that exceeds the speed of light, c, in the given medium (6
). The Cerenkov effect is analogous to the sonic boom that occurs when a macroscopic object such as a jet plane or a whip exceeds the speed of sound in air. As the charged particle travels through the medium, it loses kinetic energy by polarizing the electrons of the insulator (typically water). These polarized molecules then relax back to equilibrium through the emission of ultraviolet and visible light, and when the speed of the charged particle exceeds c, constructive interference occurs, giving the observed Cerenkov radiation (6
Although the use of Cerenkov radiation for scintillation counting has been described (8
), the use of inherent light emission of radionuclides for in vivo imaging is a new concept (12
). In a recent paper, Robertson et al. were the first to characterize the use of Cerenkov radiation for the optical imaging of 18
F-labeled radiotracers in vivo (13
). Further work by Cho et al. (14
) and Spinelli et al. (15
) verified the origins of visible light emission and paved the way for the development of Cerenkov luminescence imaging (CLI) as a novel in vivo imaging tool.
In this work, we provide further validation of the use of Cerenkov radiation from a much larger range of radionuclides including the positron emitters 18F, 64Cu, 89Zr, and 124I; β-emitter 131I; and α-particle emitter 225Ac. We report in vitro phantom studies that compare the relative intensity of the optical emission observed from these radionuclides and demonstrate the linear correlation between the observed light output and the measured PET signal. In addition, we also report the feasibility of using CLI for both the qualitative and the quantitative assessment of radiopharmaceutical uptake in tumors in vivo. Uptake of the novel monoclonal antibody (mAb)–based radiopharmaceutical 89Zr-desferrioxamine B –[DFO]-J591 for in vivo immunoimaging of prostate-specific membrane antigen (PSMA) expression in a clinically relevant model of prostate cancer was observed by standard immuno-PET and acute biodistribution studies. The results of these studies are correlated with the tumor uptake observed by CLI. These investigations reveal that optical imaging of Cerenkov radiation shows excellent promise as a potential new in vivo imaging modality for the rapid, low-cost, highthroughput screening of radiopharmaceuticals.