Eur J Nucl Med Mol Imaging (2014) 41 (Suppl 1):S36–S49 DOI 10.1007/s00259-013-2685-3 REVIEW ARTICLE The role of preclinical SPECT in oncological and neurological research in combination with either CT or MRI Monique R. Bernsen & Pieter E. B. Vaissier & Roel Van Holen & Jan Booij & Freek J. Beekman & Marion de Jong Received: 19 December 2013 /Accepted: 20 December 2013 /Published online: 17 April 2014 # The Author(s) 2014. This article is published with open access at Springerlink.com Abstract Preclinical imaging with SPECT combined with MRI are still mainly used to localize radiotracer binding and CT or MRI is used more and more frequently and has proven to improve SPECT quantification, although both CT and MRI to be very useful in translational research. In this article, an have additional potential. Future technology developments overview of current preclinical research applications and may include fast sequential or simultaneous acquisition of trends of SPECTcombined with CTor MRI, mainly in tumour (dynamic) multimodality data, spectroscopy, fMRI along with imaging and neuroscience imaging, is given and the advan- high-resolution anatomic MRI, advanced CT procedures, and tages and disadvantages of the different approaches are de- combinations of more than two modalities such as combina- scribed. Today SPECT and CT systems are often integrated tions of SPECT, PET, MRI and CT all together. This will all into a single device (commonly called a SPECT/CT system), strongly depend on new technologies. With further advances whereas at present combined SPECT and MRI is almost in biology and chemistry for imaging molecular targets and always carried out with separate systems and fiducial markers (patho)physiological processes in vivo, the introduction of to combine the separately acquired images. While preclinical new imaging procedures and promising new radiopharmaceu- SPECT/CT is most widely applied in oncology research, ticals in clinical practice may be accelerated. SPECT combined with MRI (SPECT/MRI when integrated in one system) offers the potential for both neuroscience applications and oncological applications. Today CT and Introduction M. R. Bernsen (*) : M. de Jong Department of Nuclear Medicine, Erasmus MC, Rotterdam, Over the past decade the use of PET, SPECT, CT and MRI in The Netherlands preclinical research has greatly increased due to technological e-mail: [email protected] advances that have resulted in significant improvements in spatial and temporal resolution as well as sensitivity [1–5]. M. R. Bernsen : M. de Jong Department of Radiology, Erasmus MC, Rotterdam, These noninvasive imaging methods enable imaging of The Netherlands (patho)physiological and molecular processes over time : in vivo, obviating the need for killing animals for each time- P. E. B. Vaissier F. J. Beekman point being studied [6–8]. Each of these imaging modalities Section Radiation Detection and Medical Imaging, Delft University of Technology, Delft, The Netherlands has unique qualities, in terms of their spatial and temporal resolution and their ability to measure morphology and/or R. Van Holen function; the appropriate technique should be selected accord- ELIS Department, MEDISIP, Ghent University, iMinds, ing to the research question. PET and SPECT allow detection Ghent, Belgium of radiopharmaceuticals at nano- to picomolar concentrations J. Booij in vivo, and have proven to be excellent tools in the transla- Department of Nuclear Medicine, Academic Medical Center, tional evaluation of radiotracers. CT and MRI provide a high University of Amsterdam, Amsterdam, The Netherlands degree of spatial resolution that is well suited to anatomical F. J. Beekman imaging and tissue phenotyping, including volumetry, and can MILabs B.V., Utrecht, The Netherlands provide information regarding tissue physiology [9]. Eur J Nucl Med Mol Imaging (2014) 41 (Suppl 1):S36–S49 S37 Due to their sensitive detection capabilities, PET and PET tracers in which endogenous atoms (such as hydrogen, SPECT both have preeminent ability to monitor and quantify carbon and oxygen) can be replaced by their radioactive dynamic processes at a molecular level in vivo. Unique isotopes. In addition, the dynamic capabilities of SPECT, SPECT capabilities include: the ability to image ligands such although recently greatly improved, are often limited com- as peptides and antibodies relatively easy with 99mTc, 111In or pared to those of PET. iodine isotopes (123I, 125I), the ability to measure slow kinetic In current clinical practice combining images from different processes due to the long half-life (compared to most PET tomographic modalities is common. Also in preclinical tracers) of some of the commonly used radionuclides, and the research multimodality imaging strategies are useful, as ability to probe multiple molecular pathways simultaneously different modalities can provide highly complementary by detecting radionuclides with different gamma energies information. Spatially registered images enable localiza- (multiisotope imaging). Multiisotope imaging has been tion, enhanced visualization and accurate quantification demonstrated both clinically [10–13] and preclinically of spread and uptake of radiolabelled molecules within [14, 15]. Another advantage of SPECT over PET is that the anatomical context provided by CT or MRI. In no cyclotron and associated infrastructure and complex addition, functional information derived from advanced logistics are required on site and that many tracers are CT and MRI techniques such as perfusion imaging can readily available in the form of kits. be related to expression and function of specific mole- While in clinical imaging higher spatial resolutions can be culesasmeasuredbyPETorSPECT. obtained with PET than with SPECT, the opposite is clearly In this review we discuss recent applications and techno- true in preclinical imaging in small animals. Small imaging logical advances of preclinical SPECT in combination with volumes enable the use of high magnification apertures in CT or MRI in the fields of oncology and neuroscience. Over- SPECT imaging (Fig. 1), increasing sensitivity and resolution views by others and Golestani et al. addressing preclinical relative to their clinical counterparts [16–18]. Recently devel- SPECT combined with MRI and CT in other research fields, oped SPECT systems can be extended to high-resolution such as cardiovascular research, regenerative medicine and imaging of high-energy photons emitted by PET tracers, even inflammation, have recently been published [19–22]. The simultaneously with (multiple) SPECT tracers [14]. Since space constraints of this article prevented coverage of every some SPECT systems also enable imaging of 125I-labelled aspect of this exciting field, but we aimed to provide a good tracers (<35 keV), the gap between in vitro and in vivo studies appreciation of the possibilities, and also the limitations and is closed. Finally, in SPECT imaging spatial resolution and remaining challenges. sensitivity can be adjusted by changing the size of the colli- mator apertures. On the other hand, the drawbacks of SPECT include its Applications of SPECT combined with CT or MRI lower sensitivity compared to PET, especially when high- resolution SPECT is desired. Moreover, SPECT tracer mole- Tumour imaging cules may differ with regard to their biological properties from their nonradioactive counterparts after introduction of a radio- Hanahan and Weinberg [23, 24] introduced the notion that the nuclide–chelator complex, which is not the case for several tumour microenvironment plays a crucial role in the develop- ment and behaviour of tumours, including receptiveness and sensitivity to treatment. The resulting understanding that can- cer is a complex disease with significant involvement of the tumour stroma has led to the interest in imaging tumour cell characteristics as well as noncancer cell components in vivo [25, 26], especially with regard to molecular diagnostics and drug development. Since it would be impossible to cover every aspect of this rapidly developing field, we only address some key aspects in tumour imaging and the roles that SPECT, and SPECT combined with CT or MRI have been playing in this field. Imaging targets and probes Tumours and tumour cells exhibit different characteristics Fig. 1 State-of-the-art whole-body SPECT bone images acquired for 60 min with 250 MBq 99mTc-HDP and with 0.25-mm resolution colli- compared to normal tissue and cells; this is reflected in altered mators (image courtesy of Oleksandra Ivashchenko, TU-Delft/MIlabs) physiology, tissue composition and expression of intra- and S38 Eur J Nucl Med Mol Imaging (2014) 41 (Suppl 1):S36–S49 extracellular molecules [23, 24, 26–28]. All these aspects can noninvasive tool to study candidate drugs. Especially in de- be used as imaging targets in relation to diagnostics, drug velopment of targeted treatment strategies with radiolabelled development and treatment response assessment. SPECT molecules such as peptides, antibodies and vitamin-based probes (or tracers) can be classified according to their analogues, SPECT imaging combined with CT or MRI has biodistribution and targeting characteristics, i.e. the been widely used [45, 52–56]. Next to in vivo evaluation of biodistribution of some radiopharmaceuticals is determined such molecules, SPECT combined with CT or MRI is also by their chemical/physical properties, whereas that of other being applied in the preclinical evaluation of (nano)particles tracers is determined