Challenges for the development of clinically-useful fluorescing diagnostic contrast agents for optical imaging: A radiologist's perspective

The goal of this work is to highlight those unique aspects of contrast-enhanced diagnostic optical imaging (OI) that favor a broad clinical utilization of this emerging diagnostic technique and to illustrate certain identified challenges opposing the enthusiastic clinical welcome for the OI method. We consider the single most appealing feature of OI to be its much-touted exquisite sensitivity for the detection of near-infrared fluorescing (NIRF) probes, a sensitivity supporting the development of disease- and molecule-specific NIR diagnostic probes, akin to nuclear imaging but without the ionizing radiation and with superior spatial resolution. But a qualitative OI diagnostic examination, merely defining the presence or absence of NIRF signal, may not be sufficient. The signal must be measurable. A quantitative OI examination, capable of accurately assaying the tissue concentration of the fluorescing probe and changes in that probe concentration related to disease progression or treatment would be extremely valuable. We discuss here at least three challenges to quantitative diagnostic OI, a non-linear relationship between probe concentration and signal intensity, background signal in the form of tissue auto-fluorescence, and the requirement to define precise location and depth of the signal origin from within the subject.