Why SPECT could replace PET as the standard animal imaging tool in drug discovery

The nuclear imaging technologies, PET and SPECT are highly analogous. They both offer the sensitivity required to monitor drug distribution, pharmacokinetics and pharmacodynamis, and for imaging specific biomarkers and molecular end points. Depending on the ligands and radionuclides used, a myriad of molecular end points can be visualized. Both technologies were originally developed for human use, but have recently been scaled down to allow the high-resolution imaging of animals as small as mice. This is highly relevant, because as genomics provides the drug development industry with better animal models of disease, imaging readouts can be used to evaluate novel therapeutics. In addition, both PET and SPECT fulfill the bench-to-bedside model, that is, they can be applied to mice, other rodents and primates, and can ultimately be used in clinical trials. Therefore, from the perspective of drug development, these tools can be highly valuable.

Modern small animal SPECT imagers offer superior performance.
Traditionally, PET has outperformed SPECT in terms of detection sensitivity and image resolution for human imaging applications. The use of positron emitters in PET ¬– which have higher tissue penetration than the single photon emitters used in SPECT –, and the ability to localize positrons without the use of collimation techniques, results in better detection sensitivities for imaging large subjects such as humans. However, the recent emergence of hybrid systems, PET/CT and SPECT/CT, has taken away some of the PET advantages over SPECT. Indeed, CT image data can be used to correct for tissue attenuation of SPECT emissions, and the anatomical information provided by CT further helps to improve the localization of SPECT emissions.

More importantly, for smaller subjects such as mice and other animals, the attenuation of the single photons is hardly an issue, and because of the small subject size, pinhole collimation and image magnification can be used to dramatically improve the performance of SPECT. In fact, the recent invention of multiplex multi-pinhole SPECT systems (Schramm et al, US patent 7,199,371) has resulted in the commercialization of small animal SPECT scanners with superior performance characteristics. Spatial image resolution for this new generation of animal SPECT imagers is in the nanoliter range, far superior to PET. In addition, multiple pinhole collimation systems such as used in Bioscan’s NanoSPECT/CT, provide very high imaging sensitivities putting SPECT technology on par with the best small animal PET systems. In fact, image sensitivities have improved so much that low-energy 125I-tracers can now be imaged and quantified in small animals with high resolution and sensitivity.

State-of-the-art pre-clinical SPECT imagers such as the NanoSPECT/CT enable to study and quantify drug distribution in living animals as small as mice

More economical use of SPECT tracers
The ability to image small animals with 125I tracers is highly relevant since it permits to use a large number of tracers and biomarkers without the requirement for an in-house labeling facility. Indeed, an extensive catalogue of over five hundred 125I-labelled peptides and other tracers are available commercially, which is made possible by the long half-life of 125I (59 days).

In contrast to most PET isotopes that decay much faster, many another traditional single photon emitting radioisotopes such a 99mTc, 111In, 123I and 131I have radioactive half-lives that vary from about six hours to a week, i.e., long enough to allow their production at a central site for subsequent distribution over a relatively large geographic region. This not only allows their relatively economical use in many community settings, it also makes single photon imaging agents a “gold standard” for quantifying pathophysiology in several potentially important fields of active drug development. By virtue of SPECT’s ability to probe biological processes in vivo that occur over hours or days, including the slow kinetics of endogenous biomolecules, it broadens the time window of observation and allows biologists to observe processes that span a time window from minutes to weeks. SPECT has the further unique capability of imaging two or more radio-labeled probes simultaneously which may be particularly useful when studying complex molecular interactions and the sequencing of cellular events.

The indirect costs of SPECT seem comparable to PET, as many expenses are related to regulatory compliance, quality assurance, subject accrual, medical care, and safety monitoring. However, SPECT is faster and cheaper when there is already a registered radiopharmaceutical that can suit the purpose. For example, if one needed to develop a neuroprotective drug to treat Parkinson’s disease today, a registered SPECT agent for imaging dopamine transporters is already widely used in ordinary clinical practice, whereas no PET agents are. Similarly, a new somatostatin agonist for treating cancer could use a registered SPECT agent, but there are no registered PET agents. And there are more examples for other disease targets such as cerebral perfusion agents for AD studies, myocardial perfusion tracers for cardiology studies, 99mTc phosphonates and bisphosphonates for bone disease targets, etc.

Unique Value of SPECT for Drug Discovery and Development
The ultra-high resolution nuclear imaging capabilities of state-of-the-art SPECT/CT scanners such as Bioscan’s NanoSPECT/CT system are enabling researchers to image mice with the same visual acuity as can be obtained from scanning humans with clinical scanners. Namely, researchers can now gain as much information from imaging mice as from imaging humans with clinical SPECT cameras so that pre-clinical experiments on small animals can now be carried over to humans using the same SPECT-labeled drug candidates or biomarkers. This ability is near-optimal for researchers attempting to bridge the gap between pre-clinical and clinical testing.

In addition, the longer half-live of SPECT tracers as compared to PET radioisotopes, makes SPECT a indispensable tool in the toolbox of drug developers. This could be particularly true when it becomes necessary to create a new radiopharmaceutical for a novel target. The pharmacophore from which the therapeutic candidate was derived is often from a platform with very slow biokinetics that has been deliberately designed to linger in the background tissues for relatively long periods of time to facilitate once-per-day dosing. In these cases, single photon emitting isotopes with relatively long half-lives is more useful than positron emitting versions. Also, the longer half-live of SPECT tracers offer unique advantages when the concentration of the target is relatively low. In these cases, detecting a signal sometimes requires a very low level of background noise. It can often take more time to eliminate a radiopharmaceutical from the background than positron emitting isotopes allow. In these cases, single photon emitters with longer half-lives can be very effective.

In-vivo small animal imaging with SPECT enables to conduct many drug discovery and development activities with clinically-approved biomarkers.

For pharmacokinetics studies, imaging and quantifying radiopharmaceutical uptake in vivo is an important attribute of pre-clinical imagers to speed-up drug development. Because of the relatively poor resolution of PET for imaging small animals, the partial volume effect is a significant source of quantitative error. In other words, a reduction of apparent activity concentration is observed in structures which are small compared to the resolution of the imaging device. In addition, spill-over from activity in adjacent structures due to limited resolution can further reduce the accuracy of estimating activity concentration. The sub-mm resolution capabilities of NanoSPECT and the anatomical reference images provided by the CT modality, enable state-of-the-art pre-clinical SPECT/CT imagers to obtain quantitatively accurate image reconstructions. This ability combined with the fast temporal resolution afforded by the high sensitivity of multi-pinhole SPECT imaging, makes it now possible to accurately quantify pharmacokinetics in vivo while performing longitudinal studies on the same animal.

This “new-found” ability of SPECT to perform tomographic imaging with high spatial and temporal resolution in small animals makes SPECT a very useful tool for drug development. In addition, SPECT tracers are frequently effective clinical and non-clinical tools for measuring receptor occupancy, time-on-target, and pharmacodynamic effects. Sometimes, isotopes with relatively long physical half-lives seem particularly well suited, if not required, for such work when the biologically active radiopharmaceutical has very slow kinetics. In these situations, SPECT has the potential to contribute mission-critical information to the development of new drugs. The net result could benefit the public need to enhance human research subject safety by limiting the number of volunteers who will be exposed to drugs that will ultimately fail and insuring that those who are receive the proper dose.