Applications of SmallAnimal Imagingwith PET, PET/CT,and PET/MR ImagingCristina Nanni, MDa,*, DrewA.Torigian, MD, MAb

KEYWORDS� Small animal imaging � Molecular imaging� Positron emission tomography (PET)� Computed tomography (CT)� Magnetic resonance imaging (MRI) � PET/CT � PET/MRI

Molecular imaging includes a range of techniquesmeant to visualize molecular events at the cellularlevel in living organisms in a noninvasive fashion. Inthe preclinical setting, the most interesting molec-ular imaging techniques are PET1 and MR imagingwith molecular contrast agents that allow in vivoaccurate quantitation or semiquantitation ofmany molecular phenomena. Another importanttechnique is CT with or without vascular or livercontrast agents. CT does not provide molecularinformation but is useful for observing themorphology of tissues and lesions (eg, to accu-rately measure a tumoral mass over time) becauseit is very fast and complements the data obtainedby PET and MR imaging.

It is now possible for one to purchase smallanimal PET, MR imaging, and CT scanners, butthe future includes the production of hybrid scan-ners. Currently, small animal PET/CT scanners areavailable, whereas only prototypes of PET/MRimaging scanners are available. The mostcommon way to combine data from thesemethods consists of post acquisition imagecoregistration.

Oncology is by far the field of preclinicalresearch in which all of these imaging techniquesare most frequently applied, but cardiovascularand neurologic research protocols can also take

advantage of these innovative approaches. Forexample, PET is used to provide information abouttumoral metabolic activity2,3 and allows for theexploration of different metabolic pathways inphysiologic and pathologic tissues. The mainadvantage of small animal PET and MR imagingover standard methods of preclinical experimenta-tion requiring ex vivo examination is the possibilityto analyze the same animal more than once overtime, allowing one to observe the response ofa disease condition to a new therapeutic agentor the development of disease, thereby signifi-cantly reducing the number of animals employedand increasing the reliability of the results.

Furthermore, the use of small animal PET tech-nology allows for the detection of very low (pico-molar) concentrations of radiotracers with greatsensitivity even with very small uptake variations.1

Although less sensitive than PET, MR imagingproduces high resolution imaging.

Another interesting characteristic of preclinicalmolecular imaging is summarized in the word‘‘translational.’’ By employing the same tech-nology (PET, MR imaging, or CT) in the experi-mental setting and in clinical practice, the stepbetween preclinical science and clinical applica-tions in human patients is shortened, reducingthe overall time required to effectively verify the

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a UO Medicina Nucleare, Azienda Ospedaliero-Universitaria di Bologna Policlinico S.Orsola-Malpighi, Via Mas-sarenti 9, 40138 Bologna, Italyb Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA19104, USA* Corresponding author.E-mail address: cristina.nanni@aosp.bo.it (C. Nanni).

PET Clin 3 (2009) 243–250doi:10.1016/j.cpet.2009.01.0021556-8598/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.

Nanni & Torigian244

clinical utility of a new approach. One significantexample in this field is the in vivo testing of new ra-diolabeled compounds designed to increase thespecificity of PET imaging for a specific disease.The creation of animal models of human diseasefor in vivo testing of new compounds avoids thehuman translation of compounds that do notbind to the disease site or are not specific for thedisease process of interest.

The translational applicability of these tech-niques, the possibility of accurate quantitation,3

the high spatial resolution (1 mm for PET and<1 mm for MR imaging and CT) which is veryimportant when studying small animals such asrodents in vivo, the high sensitivity, and the possi-bility of using targeted probes to increase thespecificity of disease characterization are featuresthat make these procedures desirable in thepreclinical scenario despite their relatively highcost when compared with standard ex vivostudies.

APPLICATIONS OF SMALL ANIMAL PET

In the literature, the vast majority of studies em-ploying a small animal PET scanner have notcompared the results of PET with those of otherpreclinical imaging procedures but instead takeninto consideration histochemical analyses orautoradiography to verify imaging results. Thisapproach is mainly due to the high costs of thescanners, which makes it difficult to access themultiple modality technology. In the future, morecomplementary imaging techniques will be em-ployed for evaluation of the same animal models.

Oncology

Small animal PET allows one to noninvasivelymeasure a range of tumor-relevant parameters atthe cellular and molecular level, which can beobserved longitudinally over time. Studies to eval-uate tumor response to a therapeutic interventioncan achieve statistical significance using smallergroups of animals, because tumor cell physiologyand tumor burden can be accurately determinedbefore and after therapeutic intervention.

The most widely employed PET imaging probeis [18F]-2-fluoro-2-deoxy-D-glucose (FDG), whichachieves tumor-specific accumulation becausetumor cells have a higher rate of glucose uptakeand metabolism (glycolysis) than normal tissues.FDG is generally used in oncology to predictcancer cell engraftment4 and to measure theresponse to therapy. [18F]-3’-fluoro-3’-deoxy-L-thymidine (FLT) and its analogues (eg, [18F]-1-(2’-deoxy-2’-fluoro-b-D-arabinofuranosyl)thymine)are another family of compounds that are widely

used in preclinical PET because they demonstratethe proliferative index of tumor masses with anaccuracy that is far higher for animal models ofcancer than for human patients.5

Many other PET probes have either been devel-oped or are under development to obtain tumorspecificity via a variety of tumor-specific mecha-nisms. The development of targeted radiolabeledligands has enabled PET to image many aspectsof in vivo tumor biology. Radiolabeled annexin-V,arginine-glycine-aspartic acid (RGD) peptide,vascular endothelial growth factor (VEGF), andavb3 integrin have been successfully tested intumor models as well as models of cardiac infarc-tion. The pharmacokinetics and pharmacody-namics of radiolabeled anticancer therapeuticscan, in principle, also be monitored by thesemethods, leading to rapid improvements in drugdose scheduling or design.

The effects of receptor therapies (eg, inhibitorsof androgen receptors, estrogen receptors, andepithelial growth factor receptor) can theoreticallybe predicted owing to the in vivo demonstration ofthe receptor after injection of a particular radiola-beled ligand.3

The literature includes studies on a wide numberof PET radiolabeled compounds for preclinicalevaluation of specific molecular events. It wouldbe difficult to provide a complete list of allproposed compounds for oncological studiesfrom the past decade in this article.

Cardiology

The applications of small animal PET imaging inpreclinical cardiology can basically be dividedinto measurement of myocardial viability,measurement of myocardial perfusion, measure-ment of cardiac function, and targeting of specificprocesses (eg, angiogenesis, apoptosis, and in-jected stem cells following myocardial infarction).

The imaging of myocardial viability is based onthe use of FDG. This approach relies on theconcept that all viable myocardial cells (especiallyunder conditions of hyperinsulinism) haveincreased glucose uptake. The signal obtainedfrom the heart resembles the distribution ofviability. Fibrotic and infracted areas are obviouslyhypometabolic.6,7 Regarding the evaluation ofmyocardial perfusion, [13N]-NH3 and [15O]-H2Oare suitable radiotracers for this application, andtheir use is already standard for human studies.Another possible way of assessing myocardialperfusion is to use [11C]-acetate with dynamicimage acquisition, because the myocardial bloodflow measured with [15O]-H2O and [11C]-acetateis directly correlated. Acetate has several

Small Animal Imaging with PET, PET/CT, and PET/MR Imaging 245

advantages over other tracers, including easysynthesis and a longer half-life.8

Besides studying myocardial viability and perfu-sion, it is possible to visualize other more specificcardiac processes. Angiogenesis consists of theformation of new capillaries by cellular outgrowthfrom existing microvessels. It occurs as part ofthe natural healing process after ischemic injuryand involves local proliferation and migration ofvascular smooth muscle and endothelial cells toform new capillaries. Many factors can stimulateangiogenesis, including tissue ischemia andhypoxia, inflammation, and shear stress via circu-lating angiogenic factors such as VEGF, angio-poietins, basic fibroblast growth factor,transforming growth factor, extracellular matrix,and integrins (the most important being avb3).Approaches for the targeted imaging of angiogen-esis include evaluation of the altered expression ofVEGF receptors and avb3 integrins.9

VEGF receptors can be considered as targets forimaging the mediators of ischemia-induced angio-genesis, such as through use of VEGF121 as the tar-geting ligand. [64Cu]-DOTA-VEGF121 for smallanimal PET studies was recently synthesized andtested in vivo with successful results in murine tumormodels. Another way to image angiogenesis isbased on integrins. The avb3 integrin is a protein ex-pressed in angiogenic vessels that mediates inter-cellular adhesion for all proteins with an exposedRGD tripeptide sequence. Haubner and coworkersreported the synthesis of cyclic RGD peptides thatcan be labeled with [18F]-galacto and [64Cu]-DOTA for PET studies.10 The value of the avb3

targeted imaging approach for assessment ofmyocardial angiogenesis was recently confirmed,even though most studies are based on singlephoton emitter labeled compounds. It was demon-strated that these radiotracers bind to myocardialischemicareas thathave reduced [99mTc]-sestamibiuptake.

Apoptosis, or programmed cell death, occurs inassociation with many cardiovascular diseases.Cells undergoing apoptosis express phosphatidyl-serine on their cell membranes, which is a favorabletarget for imaging.6,7 Annexin-V is a medium-sizedphysiologic human protein with a high Ca21-dependent affinity toward the phosphatidylserineon the outer leaflet of the cell membrane. Annex-in-V can be labeled with a radionuclide and usedfor apoptosis imaging. Although [99mTc]-labeledannexin-V is now available for imaging cardiacapoptosis in vivo in clinical practice (to detect smallinfarctions undetectable with [99mTc]-sestamibiand to monitor rejection in cardiac transplants),the positron emitter labeled compound [124I]-annexin-V has to date only been tested in an animal

model of hepatic apoptosis and not in the setting ofcardiac infarction.11

In recent years, the use of reporter genes tomonitor gene expression has helped in advancingthe understanding of many biologic processes.The introduction of a reporter gene within theDNA of a specific cell that must be tracked invivo leads to the production of a specific reporterprotein that becomes the specific target fora PET probe. In this way, according to the stabilityof the reporter gene, it is possible to detect theviability and location of the genetically markedcells over a long period of time (up to months).The most common approach for PET studiesinvolves the use of 9-[4-[18F]-fluoro-3-(hydroxy-methyl)butyl]-guanine as a reporter probe forimaging the enzyme-based reporter gene herpessimplex virus type 1 thymidine kinase (HSV1-tk)and its mutant derivative, HSV1-sr39tk.12

For cardiac applications, the importance of thereporter gene–reporter probe technique derivesfrom the idea of treating cardiac infarction withstem cells to prevent the left ventricle from remod-eling. After initial disappointment, it was found thatthe association of stem cells with specific growthfactors inducing their differentiation into myocytesgives good results in terms of viability and contrac-tility recovery; however, for definitive assessmentit would be necessary to ascertain in vivo cellsurvival, final location, and function.

Neurology

Owing to the small size of the brains and brainstructures of rodents, small animal PET is lessemployed in this field than in cardiology andoncology. Furthermore, anesthesia, which isessential for correct intravenous injection andimage acquisition, tends to modify the brain andbody metabolism and neurotransmitter distribu-tion and is a cause of alteration in PET tracerbiodistribution.13 To obtain meaningful images oftiny structures (eg, the basal ganglia and striato-nigral region), it is important to use high-sensitivityand high-resolution scanners, the correct anes-thesia procedure, radiotracers with high specificactivities (especially for receptor studies), andlong image acquisition times. In view of all of theissues connected with small animal PET scanningof the brain, the preclinical evaluation of neurologicdiseases in animal models is mainly based on well-established compounds, most of which areroutinely employed in clinical practice. FDG isa metabolic tracer that is used in animal modelsof Alzheimer’s disease or epilepsy (for the eva-luation of response to new therapies), highlighting

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the activity of cellular hexokinase. 6-[18F]-fluoro-L-dopa detects aromatic amino acid decarboxy-lase activity related to movement disorders,[11C]-raclopride and [18F]-fluoroethylspiperoneare receptor tracers for dopamine D2 receptors,[11C]-flumazenil binds to benzodiazepine recep-tors, and [11C]-methionine is an indicator of aminoacid transporters mainly used for the evaluation ofbrain tumors.14

APPLICATIONS OF SMALL ANIMAL PET/CT

Small animal CT can be used as a supportingmodality for small animal PET for three mainreasons. First, as in the clinical setting, it allowsthe correct anatomic localization of PET findings.This localization is of particular interest in the fieldof small animal imaging because the use of exper-imental and specific radiotracers prevents thedelineation of the animal shape from PET imagesalone. In particular, the PET image sometimesdemonstrates one or more foci of radiotraceruptake whose anatomic localization is impossiblein the absence of an anatomic reference. Second,the CT image can be used as an attenuationcorrection map for PET images, as in the clinicalsetting for humans. Because the animal body isvery small, highly energetic photons are subjectedto negligible attenuation by tissues, although it canbe important to achieve accurate quantitation ofPET radiotracer uptake when one is studyinglarger animals such as primates. Third, CT imagescan be useful to integrate the metabolic results ob-tained by PET. The CT images can be used toexactly measure the sizes or volumes of organsor tumors, with these measurements noninvasivelymonitored over time. CT also provides an attenua-tion map that can be very useful to diagnose enti-ties such as the onset of lesional necrosis, smallhepatic lesions, ascites, and so on. Small animalCT is especially useful for the evaluation ofosseous structures and the lungs, even in theabsence of intravenous contrast material.15

Recently, a technological development has ledto the possibility of acquiring CT images withcardiac or respiratory gating. Respiratory gatingis used to improve the spatial resolution predomi-nantly at the lung bases by compensating forrespiratory motion artifacts. Cardiac gating hasmuch more scientific utility. In fact, it can beused as an alternative method to measure theejection fraction for cardiac studies, because it ispossible to intravenously inject contrast agentsto allow one to differentiate the ventricular wallfrom the ventricular cavity. Such structural datacan be combined with any of the PET functionalimaging results described previously.

Most of the published studies regarding smallanimal PET/CT imaging have been performedusing two separate scanners. This technique ispossible owing to the introduction of multimodalitygantry beds which can be shifted from one scannerto the other with the same animal located upon it. Inthis way, the change in the position of the experi-mental animal is kept to a minimum, and the twoimage sets (usually in DICOM format) can besubsequently coregistered with specific software.In order to coregister a PET and CT image, it isnecessary to have at least three reference pointsto guarantee a correct slice-by-slice alignment.These reference points must be external to theanimal, radioactive for PET imaging, radiopaquefor CT imaging, and positioned on the multimodalitybed before initiation of the imaging session.

APPLICATIONS OF SMALL ANIMALPET/MR IMAGING

As small animal CT is naturally connected to thesmall animal PET scanner for physical reasonsand through the widespread use of clinical PET/CT scanners, MR imaging has been consideredas a parallel method to CT. Only in the last few yearshave attempts been made to produce PET/MRimaging hybrid scanners. These scanners are diffi-cult to integrate for several physical reasons, one ofwhich includes the potential for damage to the PETimaging components due to the high magnetic fieldof the MR imaging scanner. Despite this problem,some prototypes are already available, and it isnot impossible to predict the future developmentof these clinical and preclinical hybrid scanners.16

The relative delay in the use of MR imaging inpreclinical molecular imaging applications incomparison with other imaging techniques suchas optical imaging and PET is generally due tothe relatively low sensitivity of MR imaging todetect small amounts of targeted probes.Whereas PET can detect nanomolar concentra-tions of administered radiotracer in vivo, MRimaging can generally only visualize millimolarconcentrations of an administered probe. Consid-ering that in vivo molecular interactions occur atnanomolar concentrations, the sensitivity of MRimaging is considered suboptimal for molecularimaging, even though the high-resolutionanatomic images provided by MR imaging areuseful for imaging small animals.

In recent years, the introduction of superpara-magnetic contrast agents (superparamagneticiron oxide, very small paramagnetic iron oxide,and ultrasmall superparamagnetic iron oxide) hasincreased the number of potential applications ofMR imaging in the field of molecular imaging.

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Fig. 1. PET/MR imaging in vivo tumor study. (A) FLT PET image of BALB/c mouse bearing CT26 colon carcinomashows tumor areas with high radiotracer uptake corresponding to increased cell proliferation. (B, C) Pre- andpostcontrast enhanced T1-weighted MR images, simultaneously acquired with PET, reveal macroscopicmorphology. (D) Further analysis of contrast enhancement over time shows that the fast curve slopes and highamplitudes match areas of increased tumor proliferation on PET images. Areas in which the MR contrast agentenrichment rises slowly match areas of low FDG uptake on PET. (E, F) PET/MR images show that tumor areas ofnecrosis and inflammation have low enhancement on T1-weighted MR images and only faint FLT uptake onPET images. (Adapted from Judenhofer MS, Wehrl HF, Newport DF, et al. Simultaneous PET-MRI: a new approachfor functional and morphologic imaging. Nat Med 2008;14:461; with permission.)

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Fig. 2. PET/MR imaging in vivo brain study. (A) Dynamically acquired PET images from C57BL/6 mouse injectedwith [11C]-D-threo-methylphenidate show specific dopamine transporter binding in striatum (S) and nonspecificuptake in Harderian glands (H) (scale bars, 1 cm). (B) Simultaneously acquired three-dimensional turbo spin echoMR images reveal brain morphology (scale bars, 1 cm). (C) PET/MR images show enhanced radiotracer uptakematching morphology of striatum in MR imaging data (scale bars, 1 cm). (D) Time-activity curves, derived fromPET data simultaneously acquired during MR imaging, allow further analysis such as kinetic modeling to deter-mine dopamine transporter binding potential. Clear separation of striatum and cerebellum curves indicates morespecific radiotracer binding in striatum than in cerebellum. Note that both curves include unbound radiotracer.(Adapted from Judenhofer MS, Wehrl HF, Newport DF, et al. Simultaneous PET-MRI: a new approach for func-tional and morphologic imaging. Nat Med 2008;14:462; with permission.)

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These particles can be coupled to receptor tar-geted molecules or specific receptor ligands,creating a wide number of targeted probes formolecular imaging. Furthermore, the high numberof iron atoms held within each particle dramaticallyincreases MR imaging sensitivity for probedetection.17,18

Despite the introduction of these new targetedcontrast agents, MR and PET imaging tend notto overlap. PET radiotracers are small physiologicmolecules that can be used for the evaluation ofmetabolism as well as the analysis of tissuereceptor expression. MR imaging targeted probesare much larger and are nonphysiologic moleculeswhose true potential is still undergoing evaluation.MR imaging also has the strengths of high spatialresolution and high soft tissue contrast resolution(in particular for bone marrow and solid organs)and provides the ability to make gross measure-ments of tissue composition through the use ofmagnetic resonance spectroscopy or of tissue orlesion perfusion through the use of dynamic imageacquisition following the administration of intrave-nous contrast agents.

Based on these considerations, only a fewreports in the literature are available regardingthe combined use of both techniques for preclin-ical imaging. von Forstner and coworkers19

analyzed an animal model of pancreatic carci-noma using three different PET probes and core-gistered the PET images with MR imagesobtained on a separate scanner. MR imagingwas essentially used to delineate tumor shapeand to calculate tumor volume. Galie andcoworkers used coregistered PET and MRimaging to analyze the relationship between PETFDG uptake and MR imaging tumor perfusion.20

Lee and coworkers21 developed a bifunctionaliron oxide nanoparticle probe for PET and MRimaging scanners that, in a preliminary application,was able to detect tumor integrin avb3 expression.Despite this novel approach, two separate scan-ners were used for this application as well. Ju-denhofer and coworkers22 have developeda three-dimensional animal PET scanner builtinto a 7-T MR imaging scanner. They demon-strated that both modalities preserve their func-tionality even when operated simultaneously(Figs. 1 and 2). Although PET/MR imaging in thepreclinical setting is not yet well established, itwill continue to undergo future development.

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