The Problem is Background, not Signal

and reading articles where the tumor signal, usually a subcutaneous mass on the periphery, is barely discernable above background from the abdomen, viscera, and/or blood? This is not progress. The same is true for single-photon emission computed tomography (SPECT) radiotracers and optical imaging agents. For example, virtually every near-infrared (NIR) fl uorophore described to date has enormously high nonspecifi c tissue retention or biliary clearance, both of which lead to high background in the body, especially in the gut. Thus, although one can demonstrate receptor-specifi c uptake in artifi cial model systems such as xenograft tumors, fi nding small tumors in the abdomen or liver under realistic clinical scenarios would be nearly impossible with most optical agents. Fluorescence “quenching” until a binding or metabolic event occurs is a unique, potential background reduction strategy available to optical imaging. Conversely, autofl uorescence from endogenous fl uorophores is a unique source of background for optical imaging, but can be minimized by working with NIR wavelengths. At the Lasers in Medicine Gordon Conference in 2008, Brian Pogue from Dartmouth College showed a sobering slide, which reminded the audience that a signal to backgroundratio (SBR) ≥ 5:1 was still rare for intravenously injected exogenous contrast agents. This is abysmal. PET scanners and SPECT scanners, as well as optical imaging systems, have more than adequate sensitivity and dynamic range to achieve SBRs ≥ 100. The problem is background, not signal. So, what do we do about it? In my opinion, each fi eld within the umbrella of molecular imaging should start developing strategies to reduce nontarget tissue uptake and to maximize the elimination from the body (ie clearance) of nontarget bound contrast agents and radiotracers after intravenous injection. This is an enormously diffi cult challenge because it requires synergistic collaboration among chemists, physiologists, and imaging scientists. The fi eld has yet to devise a set of general purpose “chemical rules” to predict, a priori , which agents will work well and which will fail, or to devise coinjected agents that decrease nonspecifi c uptake and/or accelerate elimination from the body. All articles describing new diagnostic agents should also report the total W e have a lot to learn from the elder statesmen of molecular imaging. Fifty years ago, long before the term “molecular imaging” became chic, they wrestled with the problem of “background” from intravenously injected diagnostic agents, especially radiotracers. If you pull them aside at a meeting and ask them what they think the paramount problem is in the fi eld today, I suspect that most will still respond “Background. ” This problem is not modality specifi c. It underlies the inherent failure of every modality with which we now work. If molecular imaging is ever to make a major clinical impact in cancer, heart disease, and diabetes, and I would argue that we have yet to do so, it will all come down to “background reduction. ” Consider positron emission tomography (PET), for example. Commercially available clinical scanners can detect ≈ 700 Bq/voxel, which is equivalent to ≈ 0.01 radioatoms per cell. Yet, fi nding small tumors with 18 F-fl uorodeoxyglucose (FDG) and most other radiotracers remains diffi cult. The problem is neither the signal strength nor the sensitivity of the scanner; the problem is background. After intravenous injection of virtually all radiotracers described to date, including 18 FDG, the percent injected dose (%ID) taken up by nontarget tissue and remaining in the body after a few hours of clearance is extremely high. Persistent background retention (PBR) is inherent to the physicochemical properties of the diagnostic agent and can be caused by physiologic or non-physiologic binding to nontarget tissue, physiologic or non-physiologic cellular uptake in nontarget tissue, inadequate clearance from nontarget tissue, and/or metabolism in nontarget tissue. Survey the literature or posters at a meeting and you will fi nd that the order of 10%ID to 30%ID is commonly retained after intravenous injection, even when using small molecules and peptides. Are we not all weary of hearing talks The Problem is Background, not Signal