Multimodality Imaging Probes: Design and Challenges

The conundrum of modality selection in clinical diagnostic imaging is that modalities with the highest sensitivity have relatively poor resolution, while those with high resolution have relatively poor sensitivity. In recent years, the idea of using multiple modalities in conjunction has gained in popularity and researchers have come to realize that the complementary abilities of different imaging modalities could be harnessed to great effect by using them in tandem. The idea of combining imaging technologies moved to the mainstream with the advent of the first successful commercial fused instruments. The first fused PET/CT instrument, developed in 1998 by Townsend and colleagues in collaboration with Siemens Medical, was available commercially in 2001. The “Biograph” was named as one of the “Inventions of the Year” in 2000 by Time magazine, and its success was such that by 2003 fused PET/CT instruments were available from all of the major clinical instrument manufacturers, GE, Philips, CTI, and Siemens.1 Over the ensuing years, PET/CT sales increased with such vigor that by the year 2006 there were virtually no sales of standalone PET instruments; all PET sales were as part of multimodality systems.2–4 The next wave of innovation has been in PET/MRI-fused instruments, which have generated much hope for improved patient safety and imaging capability over PET/CT. Although research on PET/MRI instruments was initiated around the same time as PET/CT, the economic and engineering challenges of merging the two modalities slowed development, and the first commercial PET/MRI prototype for a human scale hybrid scanner was not unveiled until 2007.5,6 With hybrid technology clearly on the rise, the excitement over these new instruments has triggered a tumult of activity in probe design and development as investigators seek to boost the clinical benefits of hybrid instrument technology. As the preponderance of recent reviews and increase in attention at scientific meetings will attest, there has been a surge in research on multimodal contrast agent development over the past few years.5,7–17 For molecular imaging, particularly, the rise in multimodal instrumentation has sparked hopes for new ways to track multiple molecular targets simultaneously, or to use different imaging methods in combination to more clearly delineate localization and expression of biochemical markers. In the best of situations, the combined imaging methods and probes work synergistically to allow high-resolution, high-sensitivity investigation of biological activity. For example, with dual function probes for PET/MRI, the high sensitivity of PET can be used as a whole body screen to identify regions of interest, thereby reducing the volume of tissue that needs to be scanned; this reduces scan time required for high-resolution imaging by MRI.5,18 However, probe design and development has sometimes preceded the identification of clear applications that merit use of the multimodal principle. There are many literature examples of probes that are “all dressed up with nowhere to go”; they possess unique physical properties that have yet to find a clear province in medicine or biology. Nonetheless, it is not unusual for technology to sometimes presage the need, and it is these advances that can spur imaginative solutions to problems that had been intractable with the previously existing technology. The goal of multimodal functionality has already reaped benefits by driving innovation in many areas of chemical synthesis, most notably in nanotechnology. While combining multimodal detectability in the same probe is not necessitated by all applications, there can be advantages to this arrangement. A single probe helps to ensure the same pharmacokinetics and colocalization of signal for each modality if that is a concern. It also can avoid putting the additional stress on the body’s blood clearance mechanisms that can accompany administration of multiple doses of agents. The caveat is that because the sensitivities of different imaging modalities can vary by 3 orders of magnitude, it may not be practical to simply add all functionalities to one molecule, although we will see that is a common design, because the requirements for contrast agent concentrations can be vastly different between modalities. In this review, we provide an overview of the many strategies that have been applied to achieve multimodal functionality in a single probe unit. These span the range from small molecule to nanoparticulate systems and vary in complexity from facile encapsulation or conjugation of commercially available probes to de novo synthesis. This review is limited to reports from the last approximately 5 years that deal with agents that carry two or more species of contrast enhancers. Tables summarizing the physical properties from cited articles are included with each major category of probe to facilitate “browsing” by the reader.