Curr Cardiol Rep (2015) 17: 28 DOI 10.1007/s11886-015-0581-0
CARDIAC PET, CT, AND MRI (SE PETERSEN, SECTION EDITOR)
Cardiac PET for Translational Imaging C. Rischpler & Anna Paschali & Constantinos Anagnostopoulos & S. G. Nekolla
Published online: 18 April 2015 # Springer Science+Business Media New York 2015
Abstract All along, translational cardiovascular research has been dependent on non-invasive imaging (such as singlephoton emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT), echocardiography, or magnetic resonance imaging (MRI)), as these techniques allow the assessment of surrogate markers in intact living organisms non-invasively. PET offers the advantages of high sensitivity; the capability for longitudinal, quantitative imaging; and that an armamentarium of promising radiotracers is readily available. All commercially available PET scanners are equipped with a CT component, and thus, the often cited disadvantage of a lack of morphologic correlation does not really count anymore. This review aims to give an outline on PET as a promising tool for translational research in cardiology as dedicated preclinical systems with virtually the same imaging features as those used in clinical imaging allows the straightforward concept of Bbench to bedside.^ Keywords PET . PET/CT . Translational research . Molecular imaging
This article is part of the Topical Collection on Cardiac PET, CT, and MRI C. Rischpler : S. G. Nekolla (*) Nuklearmedizinische Klinik der TU München, Munchen, Germany e-mail: [email protected] C. Rischpler e-mail: [email protected] A. Paschali : C. Anagnostopoulos Biomedical Research Foundation Academy of Athens, Athens, Greece A. Paschali e-mail: [email protected] C. Anagnostopoulos e-mail: [email protected]
Introduction The transition of a novel modality, application, medication, or therapy from Bbench to bedside^ is often referred to as Btranslational medicine.^ Obviously, the aim of translational medicine is to enhance human health including prevention, diagnosis, and therapy of diseases. BTranslational imaging^ often plays a crucial role in this transition as it allows to non-invasively and longitudinally obtain data (both in animals and in humans) of ongoing processes in a whole, intact organism. Also, imaging modalities allow to quantify certain surrogate parameters— e.g., in the cardiac field global parameters such as left ventricular function (EDV, ESV, EF) and wall motion abnormalities or on the molecular basis such as myocardial perfusion, viability, inflammation, innervation, apoptosis, or neovascularization. In recent years, there was a substantial progress in the development of imaging agents targeting cells or even molecules, which also resulted in the creation of a novel, multidisciplinary research field termed Bmolecular imaging^ (just an aside: even the former Society of Nuclear Medicine adapted its name to BSociety of Nuclear Medicine and Molecular Imaging^). This will ultimately result in a multitude of novel imaging probes which will of course also affect the cardiovascular field. However, there are certain requirements that have to be fulfilled by any imaging agents such as lack of toxicity, favorable pharmacokinetics and biodistribution properties, reliable synthesis, and high binding specificity. Consequentially, many potential and promising tracers will not fulfill all criteria and thus will not make it to the clinics, which results in high developmental cost. When designing a new tracer, it is obviously of high importance to identify an appropriate target—this includes cells, receptors, proteins, or even the DNA. As cells are very rich in proteins (compared to the much lower number
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of, e.g., RNA or DNA), they represent usually a very promising target [1•]. Due to their excellent sensitivity, nuclear imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) are often advantageous over morphological imaging modalities (such as ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI)) regarding the detection of signals on a molecular level. However, PET and SPECT suffer from a rather poor spatial resolution and are often not suitable for morphological correlation particularly in the case of highly specific tracers with low non-specific binding. Consequentially, there is a trend towards the construction of hybrid scanners (such as PET/CT, SPECT/CT, PET/MR, or PET/SPECT/CT), and, nowadays, standalone PETs are even not constructed anymore by major vendors. These hybrid scanners do not only benefit from an increased sensitivity and spatial resolution but also from the simultaneous acquisition of function and morphology. Cardiac imaging is in the favorable position to utilize this increased availability of those systems both clinically as well as preclinically due its wide utilization in oncological imaging. This review aims to give a brief, conceptional overview on the PET technique and will then focus on imaging applications that have been recently successfully translated or about to be translated into clinics. Also, we will briefly outline techniques that are still only available in a preclinical setting.
Positron Emission Tomography For PET, usually radionuclides with short half-lives such as rubidium-82 (Rb-82, T½ ≈78 s), oxygen-15 (O-15, T½ ≈2.1 min), nitrogen-13 (N-13, T½ ≈10 min), carbon-11 (C-11, T½ ≈20 min), gallium-68 (Ga-68, T½ ≈68 min), or fluorine-18 (F-18, T½ ≈110 min) are used to label carrier molecules. The carrier molecule has to be chosen based on the (patho-)physiologic condition that is supposed to be investigated (e.g., perfusion, innervation, viability, apoptosis, etc.). While O-15, N-13, F-18, and C-11 are produced using a cyclotron, Rb-82 and Ga-68 are produced from a strontium-82 (Sr-82)-generator or a Germanium-68 (Ge-68)-generator, respectively. After the radioactive decay, the positron travels a certain range (in the order of a few millimeters) depending on the intrinsic kinetic energy of the emitted positron. The higher the energy of the emitted positron, the higher the distance until the positron annihilates with an electron and emits two 511keV photon which travel in diametrically opposed directions (≈180°). Thus, in contrast to SPECT scanners where lead collimators are used to associate a detected event with the direction it came from, PET is using an Belectronic collimation,^ increasing its spatial resolution and its sensitivity as no
Curr Cardiol Rep (2015) 17: 28
photons are lost within heavy collimators (although the needed hardware is clearly more expensive). However, as the PET detectors detect the two 511-keV photon in coincidence, a high positron energy results in reduced spatial resolution. Of course, higher positron energy has also the disadvantage of an increased radiation burden. Thus, the choice of isotope has to be carefully considered in the imaging of small animals, in particular mice. The PET images are then calculated from many millions of these detected coincidences. Each of them form a so-called line-of-response, and after resorting these into projections, a subsequent mathematical reconstruction will generate tomographic images. It is important to note that this imaging approach is truly volumetric, as many hundreds of crystals are located around the imaging target. The typical field of view in clinical systems is between 15 and 25 cm so the cardiac systems are fully covered. The advantages of the PET technique are high sensitivity and temporal resolution, which allow for dynamic imaging and absolute quantification of physiological processes. Furthermore, if data are acquired in the so-called list mode, images can be corrected for cardiac and respiratory motion [2]. The spatial resolution of state-of-the-art PET scanners for clinical use is in the range of 3–5 mm. The resolution of PET systems is limited by both the physical properties of the positron (including the not exact diametrical photon emission process after annihilation) and the size of the detection crystals [3]. However, the disadvantages of PET are not only the high cost for the purchase of the scanner but also the expensive construction of an on-site cyclotron or the constant need to purchase a generator. Besides the favorable radiochemical properties (such as a low kinetic energy of the positron), the main reason why F-18-labeled tracers are usually preferred is the following: with a half-life of almost 2 h, fluorinated tracers may be delivered even to remote sites making an on-site cyclotron not essential, while other cyclotron-dependent tracers such as C-11-, N-13-, or O-15-labeled agents can only be used in close proximity. The concept of translational imaging is facilitated with the so-called micro-PET systems which are readily available for preclinical imaging. These scanners have a bore size in the range of 10–20 cm and are equipped with small detection crystals, resulting in an acceptable resolution for small animals of about 1–2 mm with an axial field-of-view between 5 and 10 cm [4, 5]. The first of its kind was installed only in 1996 at the UCLA in California; today, more than 80 small-animal PET scanners are distributed all over the world.
PET-Based Assessment of Biological Processes Myocardial Perfusion The assessment of myocardial perfusion in resting and under stress conditions is one of the most widely used imaging
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procedures with high clinical relevance. There are several PET perfusion tracers available. The most widely used and clinically available tracers are N-13 ammonia, Rb-82, and O-15 water [6•]. Rb-82 has been approved by the FDA in 1989 for the diagnosis of CAD and has been reimbursed by the Health Care Financing Administration since 1995. Since then, it has become the most commonly applied PET myocardial perfusion tracer in the USA. It is a potassium analog—similar to thallium-201—and is taken up by the cardiomyocytes via the Na+/K+/ATPase. Another FDA-approved myocardial perfusion imaging (MPI) PET tracer is N-13 ammonia. N-13 ammonia is trapped inside the cardiomyocytes as N-13 glutamine and has the advantage over Rb-82 of a higher extraction fraction. The third PET perfusion agent, O-15 water, is a freely diffusible tracer and thus has the advantage of an extraction fraction of 100%. The disadvantage of this property is, however, that no direct images are available and only myocardial (parametric) data can be obtained after application of kinetic modeling techniques. Consequentially, O-15 water is usually used in preclinical settings—only a few institutions worldwide perform O-15 water PET MPI in daily clinical routine. Usually, PET MPI is performed at rest and during pharmacological stress (using either adenosine/regadenoson or dobutamine). For the detection of flow-limiting coronary artery disease, PET represents an excellent technique with sensitivity and specificity of about 90 % [7]. As mentioned above, F-18-labeled tracers have particular advantages with respect to image quality and logistics. Therefore, expectations were high when F-18 flurpiridaz—a novel PET MPI tracer which targets the enzyme NADH:ubiquinone oxidoreductase of the mitochondrial complex I—was introduced. The bench-to-beside path of this agent is an excellent example of the advantages of PET [8•]. Starting with the evaluation in an isolated rat heart model and showing the high extraction even under high flows [9], infarct models in the rat were investigated [10, 11]. This research was performed using preclinical PET systems. In the next step, our group performed the first scan in a large animal model using a clinical scanner [12] to demonstrate its applicability in a close to human setting (Fig. 1). Finally, Maddahi et al. performed a phase 1 study evaluating image characteristics, kinetics, and dosimetry [13].
Fig. 1 Cardiac PET imaging of myocardial tracer uptake using F-18-labeled tracers in mouse, rat, pig, and man. The short axis images were acquired in a dedicated animal PET/CT (mouse, rat) and a clinical PET/ CT tomograph (pig, man)
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In all these studies, F-18 flurpiridaz shows consistently favorable imaging characteristics such as rapid and stable uptake by cardiomyocytes, prolonged retention, and even superior extraction. Also, the first phase II study results proved that this radiotracer has superior properties regarding sensitivity, image quality, and diagnostic certainty over SPECT MPI [14]. Preliminary results that were announced in October 2013 were disappointing, however. While F-18 flurpiridaz outperformed SPECT MPI in the detection of CAD, it showed inferior specificity. Due to this setback, research activities and interest in alternative PET MPI tracers may raise again. Promising candidates, which have been investigated only preclinically so far, are F-18-fluorobenzyl triphenyl phosphonium (F-18FBnTP) and C-11-dimethyl-diphenyl-ammonium (C-11DMDPA). F-18-FBnTP, which also targets the mitochondria, has already been studied successfully in small and in large animal models and showed promising characteristics such as fast and stable uptake into cardiomyocytes, rapid tracer washout from the lung, and fast clearing from the blood pool [15]. C-11-DMDPA belongs to the family of ammonium salts and was already studied in large animals too [16]. Also, this tracer showed superior imaging quality compared to N-13 ammonia in rats [17]. It remains to be seen if these tracers will make the final leap into the clinical arena. Myocardial Metabolism The most commonly used tracer to assess myocardial glucose metabolism is F-18 fluorodeoxyglucose (F-18-FDG). As a glucose analog, it is enriched in cells by glucose transporters (GLUTs). Consequentially, it enters cardiomyocytes primarily via GLUT1 and 4 and is subsequently trapped inside the cell by a phosphorylation reaction through the hexokinase (to F-18-glucose-6-phosphate). In contrast to glucose-6-phosphate, the fluorinated version of this metabolite is not metabolized further. Therefore, F-18-glucose-6-phosphate enriches in and is trapped inside the cell. Still, F-18-FDG is considered the gold standard for myocardial viability assessment [18]. A disadvantage of F-18-FDG is, however, that it is not exclusively taken up not only by cardiomyocytes but also by a large variety of cells (e.g., tumor and inflammatory cells). Recently, research also applied F-18-FDG for the assessment of the
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inflammatory reaction within the myocardium after acute myocardial infarction [19] (Fig. 2). Other tracers that have been used for myocardial metabolism imaging are C-11 palmitic acid and C-11 acetate. The oxidation of long-chain fatty acids is the major source of cardiac energy. Due to complex kinetics and back-diffusion of the unmetabolized tracer, however, only semiquantitative assessment is feasible. C-11 acetate enters the tricarboxylic acid cycle and is metabolized to carbon dioxide. It is therefore a marker of general oxidative metabolism [20]. Another interesting property of this tracer is that, it is initially taken up in proportion to the myocardial blood flow. Therefore, in theory, both myocardial perfusion and oxidative metabolism can be assessed in a single imaging session. Myocardial Innervation A variety of PET tracers are (theoretically) available to assess the innervation of the myocardium. The most commonly used PET tracer is C-11 hydroxyephedrine (C-11-HED). It is— similar to meta-iodobenzylguanidine (MIBG)—a norepinephrine analog and preeminently taken up into sympathetic nerve terminals by the noradrenaline transporter. It is neither metabolized by the monoamine oxidase (MAO) nor by the catecholO-methyltransferase (COMT) and shows only a small proportion of non-specific type-2 transport [21]. Most human studies have been carried out with C-11-HED. Recently, it was observed that sympathetic denervation (which was assessed by C-11-HED PET) is an independent predictor of sudden cardiac death independently from ejection fraction and infarct
Fig. 2 F-18-FDG PET imaging in rat and man shortly after myocardial infarction and reperfusion corresponding to inflammation and/or a change in myocardial metabolism. The late gadolinium enhancement MR images show a matching diffuse uptake indicating a different volume of distribution for this MR contrast agent pointing to local edema. For the rodent images, a preclinical PET and a 7-T preclinical MRI was used. The human data were created on a fully integrated PET/MRI system
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volume in patients suffering from ischemic cardiomyopathy [22]. Therefore, C-11-HED PET could be favorable to identify those patients which benefit most from implantable cardioverter defibrillator (ICD) implantation. Another mostly preclinically used radiotracer is C-11 epinephrine (C-11-EPI). In contrast to C-11-HED, C-11-EPI is metabolized by MAO and, thus, considered to have superior properties as it reflects the whole pathway of catecholamine uptake, degradation, and vesicular storage. Regardless of these favorable characteristics, this tracer has mainly been used in animal studies [23] and only few studies in humans have been reported [24]. The third commonly studied radiotracer for evaluation of the cardiac innervation is C-11 phenylephrine (C-11-PHEN). Similar to C-11-EPI, it is metabolized by MAO and the resulting metabolite—C-11 methylamine—washes out rapidly from the nerve terminal. Under normal conditions, C-11PHEN shows a faster efflux than C-11-HED from the storage vesicles. Consequentially, C-11-PHEN may be used to assess the vesicular leakage [25]. Initial uptake images of C-11-HED and C-11-PHEN are similar; however, the washout of C-11PHEN is considerably faster [26]. The functional integrity of the neuronal innervation of the heart may be estimated by calculating the storage half-life using C-11-PHEN. A potentially very attractive example of successful translation of a radiotracer from bench to bedside is N-[3-bromo4-(3-[F-18]fluoro-propoxy)-benzyl]-guanidine (LMI1195). This radiotracer was designed using a similar structure as I-123-MIBG, a SPECT tracer for the norepinephrine transporter. I-123-MIBG has been proven to be valuable in many clinical studies, particularly in patients with heart failure, with the aim to identify those subjects who would profit from ICD implantation [27]. Between the first reported use in cells and animals [28] and the first published investigation in humans just lie 3 years [29]. As the image quality is far above I-123MIBG, its clinical availability is of high interest (Fig. 3).
Fig. 3 F-18-LMI1195 as a marker of sympathetic innervation. The rabbit data where created on a fully integrated PET/MRI system in a simultaneous measurement
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Besides the aforementioned agents, there are also radiotracers that allow the assessment of the postsynaptic receptor density. The non-invasive quantification of cardiac βadrenoceptors is of high clinical interest as it is known that numerous pathophysiological conditions (such as hypertension, heart failure, ischemia, or various cardiomyopathies) have an influence on the density of those receptors. Examples of radiotracers that have been used for this purpose are C-11-CGP12177, C-11 carazolol, or F-18 fluorocarazolol [30]. Muscarinic receptors, which are known to play a pivotal role in the regulation of the heart cycle, have also been studied in some studies and one of the most promising radiotracers is C-11 methylquinuclidinylbenzilate (C-11-MQNB) [31]. Other Potential Targets Most of the tracers mentioned above have at least partly been translated to the human use. However, there are still some agents that will have to prove their potential in humans. Neoangiogenesis One tracer that was promising in small animal studies is 18Fgalacto-arginine-glycine-aspartate (RGD). This tracer has high affinity to αvβ3 integrin receptors which are known to be overexpressed on the endothelial surface during neoangiogenesis. Recently, gallium-68-labeled RGD tracers have been developed, e.g., Ga-68-NOTA-RGD [32]. Ga-68 is a radionuclide that is particularly interesting for PET centers without an installed cyclotron as it is produced from commercially available germanium-68 generator system. Apoptosis The most frequently studied tracer for apoptosis is annexin-V. This tracer binds with high specificity to phosphatidylserine, which is overexpressed on apoptotic cells. For radiolabeling of this molecule with positron emitters, both C-11 and Ga-68 have been used. This tracer has recently been investigated for the evaluation of parathyroid hormone treatment in a mouse model of myocardial infarction [33]. While initial results using annexin-V tracers for apoptosis imaging in animals were feasible and also some clinical studies have been conducted, the final transition into human is still pending.
Conclusions Besides an unmet clinical need for non-invasive imaging, several prerequisites are necessary for a successful transition of novel molecular imaging approaches into clinics: technological development, suitable animal models, and development of probes. Nuclear imaging—and particularly PET—offers some
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advantages over other imaging modalities which include the very high sensitivity, a wide armamentarium of probes as well as the ongoing development of new agents, and the good availability of imaging devices. Disadvantages in PET imaging are, however, the relatively low spatial resolution, the ionizing radiation burden, the lack of detailed morphologic information, and the high costs for radionuclide production (either by generator or cyclotron). Some issues have already been resolved by the combination of different imaging modalities resulting in hybrid scanners such as PET/CT or PET/MR. Another hurdle that should not be underestimated are the regulatory burdens—particularly in many countries of the Western societies—that need to be overcome until a promising probe can finally make it into clinics. However, if one makes it to overcome all these stumbling blocks, PET is one of the most promising techniques for translational research nowadays. Compliance with Ethics Guidelines Conflict of Interest C. Rischpler, Anna Paschali, Constantinos Anagnostopoulos, and S.G. Nekolla declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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CARDIAC PET, CT, AND MRI (SE PETERSEN, SECTION EDITOR)
Cardiac PET for Translational Imaging C. Rischpler & Anna Paschali & Constantinos Anagnostopoulos & S. G. Nekolla
Published online: 18 April 2015 # Springer Science+Business Media New York 2015
Abstract All along, translational cardiovascular research has been dependent on non-invasive imaging (such as singlephoton emission computed tomography (SPECT), positron emission tomography (PET), computed tomography (CT), echocardiography, or magnetic resonance imaging (MRI)), as these techniques allow the assessment of surrogate markers in intact living organisms non-invasively. PET offers the advantages of high sensitivity; the capability for longitudinal, quantitative imaging; and that an armamentarium of promising radiotracers is readily available. All commercially available PET scanners are equipped with a CT component, and thus, the often cited disadvantage of a lack of morphologic correlation does not really count anymore. This review aims to give an outline on PET as a promising tool for translational research in cardiology as dedicated preclinical systems with virtually the same imaging features as those used in clinical imaging allows the straightforward concept of Bbench to bedside.^ Keywords PET . PET/CT . Translational research . Molecular imaging
This article is part of the Topical Collection on Cardiac PET, CT, and MRI C. Rischpler : S. G. Nekolla (*) Nuklearmedizinische Klinik der TU München, Munchen, Germany e-mail: [email protected] C. Rischpler e-mail: [email protected] A. Paschali : C. Anagnostopoulos Biomedical Research Foundation Academy of Athens, Athens, Greece A. Paschali e-mail: [email protected] C. Anagnostopoulos e-mail: [email protected]
Introduction The transition of a novel modality, application, medication, or therapy from Bbench to bedside^ is often referred to as Btranslational medicine.^ Obviously, the aim of translational medicine is to enhance human health including prevention, diagnosis, and therapy of diseases. BTranslational imaging^ often plays a crucial role in this transition as it allows to non-invasively and longitudinally obtain data (both in animals and in humans) of ongoing processes in a whole, intact organism. Also, imaging modalities allow to quantify certain surrogate parameters— e.g., in the cardiac field global parameters such as left ventricular function (EDV, ESV, EF) and wall motion abnormalities or on the molecular basis such as myocardial perfusion, viability, inflammation, innervation, apoptosis, or neovascularization. In recent years, there was a substantial progress in the development of imaging agents targeting cells or even molecules, which also resulted in the creation of a novel, multidisciplinary research field termed Bmolecular imaging^ (just an aside: even the former Society of Nuclear Medicine adapted its name to BSociety of Nuclear Medicine and Molecular Imaging^). This will ultimately result in a multitude of novel imaging probes which will of course also affect the cardiovascular field. However, there are certain requirements that have to be fulfilled by any imaging agents such as lack of toxicity, favorable pharmacokinetics and biodistribution properties, reliable synthesis, and high binding specificity. Consequentially, many potential and promising tracers will not fulfill all criteria and thus will not make it to the clinics, which results in high developmental cost. When designing a new tracer, it is obviously of high importance to identify an appropriate target—this includes cells, receptors, proteins, or even the DNA. As cells are very rich in proteins (compared to the much lower number
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of, e.g., RNA or DNA), they represent usually a very promising target [1•]. Due to their excellent sensitivity, nuclear imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) are often advantageous over morphological imaging modalities (such as ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI)) regarding the detection of signals on a molecular level. However, PET and SPECT suffer from a rather poor spatial resolution and are often not suitable for morphological correlation particularly in the case of highly specific tracers with low non-specific binding. Consequentially, there is a trend towards the construction of hybrid scanners (such as PET/CT, SPECT/CT, PET/MR, or PET/SPECT/CT), and, nowadays, standalone PETs are even not constructed anymore by major vendors. These hybrid scanners do not only benefit from an increased sensitivity and spatial resolution but also from the simultaneous acquisition of function and morphology. Cardiac imaging is in the favorable position to utilize this increased availability of those systems both clinically as well as preclinically due its wide utilization in oncological imaging. This review aims to give a brief, conceptional overview on the PET technique and will then focus on imaging applications that have been recently successfully translated or about to be translated into clinics. Also, we will briefly outline techniques that are still only available in a preclinical setting.
Positron Emission Tomography For PET, usually radionuclides with short half-lives such as rubidium-82 (Rb-82, T½ ≈78 s), oxygen-15 (O-15, T½ ≈2.1 min), nitrogen-13 (N-13, T½ ≈10 min), carbon-11 (C-11, T½ ≈20 min), gallium-68 (Ga-68, T½ ≈68 min), or fluorine-18 (F-18, T½ ≈110 min) are used to label carrier molecules. The carrier molecule has to be chosen based on the (patho-)physiologic condition that is supposed to be investigated (e.g., perfusion, innervation, viability, apoptosis, etc.). While O-15, N-13, F-18, and C-11 are produced using a cyclotron, Rb-82 and Ga-68 are produced from a strontium-82 (Sr-82)-generator or a Germanium-68 (Ge-68)-generator, respectively. After the radioactive decay, the positron travels a certain range (in the order of a few millimeters) depending on the intrinsic kinetic energy of the emitted positron. The higher the energy of the emitted positron, the higher the distance until the positron annihilates with an electron and emits two 511keV photon which travel in diametrically opposed directions (≈180°). Thus, in contrast to SPECT scanners where lead collimators are used to associate a detected event with the direction it came from, PET is using an Belectronic collimation,^ increasing its spatial resolution and its sensitivity as no
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photons are lost within heavy collimators (although the needed hardware is clearly more expensive). However, as the PET detectors detect the two 511-keV photon in coincidence, a high positron energy results in reduced spatial resolution. Of course, higher positron energy has also the disadvantage of an increased radiation burden. Thus, the choice of isotope has to be carefully considered in the imaging of small animals, in particular mice. The PET images are then calculated from many millions of these detected coincidences. Each of them form a so-called line-of-response, and after resorting these into projections, a subsequent mathematical reconstruction will generate tomographic images. It is important to note that this imaging approach is truly volumetric, as many hundreds of crystals are located around the imaging target. The typical field of view in clinical systems is between 15 and 25 cm so the cardiac systems are fully covered. The advantages of the PET technique are high sensitivity and temporal resolution, which allow for dynamic imaging and absolute quantification of physiological processes. Furthermore, if data are acquired in the so-called list mode, images can be corrected for cardiac and respiratory motion [2]. The spatial resolution of state-of-the-art PET scanners for clinical use is in the range of 3–5 mm. The resolution of PET systems is limited by both the physical properties of the positron (including the not exact diametrical photon emission process after annihilation) and the size of the detection crystals [3]. However, the disadvantages of PET are not only the high cost for the purchase of the scanner but also the expensive construction of an on-site cyclotron or the constant need to purchase a generator. Besides the favorable radiochemical properties (such as a low kinetic energy of the positron), the main reason why F-18-labeled tracers are usually preferred is the following: with a half-life of almost 2 h, fluorinated tracers may be delivered even to remote sites making an on-site cyclotron not essential, while other cyclotron-dependent tracers such as C-11-, N-13-, or O-15-labeled agents can only be used in close proximity. The concept of translational imaging is facilitated with the so-called micro-PET systems which are readily available for preclinical imaging. These scanners have a bore size in the range of 10–20 cm and are equipped with small detection crystals, resulting in an acceptable resolution for small animals of about 1–2 mm with an axial field-of-view between 5 and 10 cm [4, 5]. The first of its kind was installed only in 1996 at the UCLA in California; today, more than 80 small-animal PET scanners are distributed all over the world.
PET-Based Assessment of Biological Processes Myocardial Perfusion The assessment of myocardial perfusion in resting and under stress conditions is one of the most widely used imaging
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procedures with high clinical relevance. There are several PET perfusion tracers available. The most widely used and clinically available tracers are N-13 ammonia, Rb-82, and O-15 water [6•]. Rb-82 has been approved by the FDA in 1989 for the diagnosis of CAD and has been reimbursed by the Health Care Financing Administration since 1995. Since then, it has become the most commonly applied PET myocardial perfusion tracer in the USA. It is a potassium analog—similar to thallium-201—and is taken up by the cardiomyocytes via the Na+/K+/ATPase. Another FDA-approved myocardial perfusion imaging (MPI) PET tracer is N-13 ammonia. N-13 ammonia is trapped inside the cardiomyocytes as N-13 glutamine and has the advantage over Rb-82 of a higher extraction fraction. The third PET perfusion agent, O-15 water, is a freely diffusible tracer and thus has the advantage of an extraction fraction of 100%. The disadvantage of this property is, however, that no direct images are available and only myocardial (parametric) data can be obtained after application of kinetic modeling techniques. Consequentially, O-15 water is usually used in preclinical settings—only a few institutions worldwide perform O-15 water PET MPI in daily clinical routine. Usually, PET MPI is performed at rest and during pharmacological stress (using either adenosine/regadenoson or dobutamine). For the detection of flow-limiting coronary artery disease, PET represents an excellent technique with sensitivity and specificity of about 90 % [7]. As mentioned above, F-18-labeled tracers have particular advantages with respect to image quality and logistics. Therefore, expectations were high when F-18 flurpiridaz—a novel PET MPI tracer which targets the enzyme NADH:ubiquinone oxidoreductase of the mitochondrial complex I—was introduced. The bench-to-beside path of this agent is an excellent example of the advantages of PET [8•]. Starting with the evaluation in an isolated rat heart model and showing the high extraction even under high flows [9], infarct models in the rat were investigated [10, 11]. This research was performed using preclinical PET systems. In the next step, our group performed the first scan in a large animal model using a clinical scanner [12] to demonstrate its applicability in a close to human setting (Fig. 1). Finally, Maddahi et al. performed a phase 1 study evaluating image characteristics, kinetics, and dosimetry [13].
Fig. 1 Cardiac PET imaging of myocardial tracer uptake using F-18-labeled tracers in mouse, rat, pig, and man. The short axis images were acquired in a dedicated animal PET/CT (mouse, rat) and a clinical PET/ CT tomograph (pig, man)
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In all these studies, F-18 flurpiridaz shows consistently favorable imaging characteristics such as rapid and stable uptake by cardiomyocytes, prolonged retention, and even superior extraction. Also, the first phase II study results proved that this radiotracer has superior properties regarding sensitivity, image quality, and diagnostic certainty over SPECT MPI [14]. Preliminary results that were announced in October 2013 were disappointing, however. While F-18 flurpiridaz outperformed SPECT MPI in the detection of CAD, it showed inferior specificity. Due to this setback, research activities and interest in alternative PET MPI tracers may raise again. Promising candidates, which have been investigated only preclinically so far, are F-18-fluorobenzyl triphenyl phosphonium (F-18FBnTP) and C-11-dimethyl-diphenyl-ammonium (C-11DMDPA). F-18-FBnTP, which also targets the mitochondria, has already been studied successfully in small and in large animal models and showed promising characteristics such as fast and stable uptake into cardiomyocytes, rapid tracer washout from the lung, and fast clearing from the blood pool [15]. C-11-DMDPA belongs to the family of ammonium salts and was already studied in large animals too [16]. Also, this tracer showed superior imaging quality compared to N-13 ammonia in rats [17]. It remains to be seen if these tracers will make the final leap into the clinical arena. Myocardial Metabolism The most commonly used tracer to assess myocardial glucose metabolism is F-18 fluorodeoxyglucose (F-18-FDG). As a glucose analog, it is enriched in cells by glucose transporters (GLUTs). Consequentially, it enters cardiomyocytes primarily via GLUT1 and 4 and is subsequently trapped inside the cell by a phosphorylation reaction through the hexokinase (to F-18-glucose-6-phosphate). In contrast to glucose-6-phosphate, the fluorinated version of this metabolite is not metabolized further. Therefore, F-18-glucose-6-phosphate enriches in and is trapped inside the cell. Still, F-18-FDG is considered the gold standard for myocardial viability assessment [18]. A disadvantage of F-18-FDG is, however, that it is not exclusively taken up not only by cardiomyocytes but also by a large variety of cells (e.g., tumor and inflammatory cells). Recently, research also applied F-18-FDG for the assessment of the
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inflammatory reaction within the myocardium after acute myocardial infarction [19] (Fig. 2). Other tracers that have been used for myocardial metabolism imaging are C-11 palmitic acid and C-11 acetate. The oxidation of long-chain fatty acids is the major source of cardiac energy. Due to complex kinetics and back-diffusion of the unmetabolized tracer, however, only semiquantitative assessment is feasible. C-11 acetate enters the tricarboxylic acid cycle and is metabolized to carbon dioxide. It is therefore a marker of general oxidative metabolism [20]. Another interesting property of this tracer is that, it is initially taken up in proportion to the myocardial blood flow. Therefore, in theory, both myocardial perfusion and oxidative metabolism can be assessed in a single imaging session. Myocardial Innervation A variety of PET tracers are (theoretically) available to assess the innervation of the myocardium. The most commonly used PET tracer is C-11 hydroxyephedrine (C-11-HED). It is— similar to meta-iodobenzylguanidine (MIBG)—a norepinephrine analog and preeminently taken up into sympathetic nerve terminals by the noradrenaline transporter. It is neither metabolized by the monoamine oxidase (MAO) nor by the catecholO-methyltransferase (COMT) and shows only a small proportion of non-specific type-2 transport [21]. Most human studies have been carried out with C-11-HED. Recently, it was observed that sympathetic denervation (which was assessed by C-11-HED PET) is an independent predictor of sudden cardiac death independently from ejection fraction and infarct
Fig. 2 F-18-FDG PET imaging in rat and man shortly after myocardial infarction and reperfusion corresponding to inflammation and/or a change in myocardial metabolism. The late gadolinium enhancement MR images show a matching diffuse uptake indicating a different volume of distribution for this MR contrast agent pointing to local edema. For the rodent images, a preclinical PET and a 7-T preclinical MRI was used. The human data were created on a fully integrated PET/MRI system
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volume in patients suffering from ischemic cardiomyopathy [22]. Therefore, C-11-HED PET could be favorable to identify those patients which benefit most from implantable cardioverter defibrillator (ICD) implantation. Another mostly preclinically used radiotracer is C-11 epinephrine (C-11-EPI). In contrast to C-11-HED, C-11-EPI is metabolized by MAO and, thus, considered to have superior properties as it reflects the whole pathway of catecholamine uptake, degradation, and vesicular storage. Regardless of these favorable characteristics, this tracer has mainly been used in animal studies [23] and only few studies in humans have been reported [24]. The third commonly studied radiotracer for evaluation of the cardiac innervation is C-11 phenylephrine (C-11-PHEN). Similar to C-11-EPI, it is metabolized by MAO and the resulting metabolite—C-11 methylamine—washes out rapidly from the nerve terminal. Under normal conditions, C-11PHEN shows a faster efflux than C-11-HED from the storage vesicles. Consequentially, C-11-PHEN may be used to assess the vesicular leakage [25]. Initial uptake images of C-11-HED and C-11-PHEN are similar; however, the washout of C-11PHEN is considerably faster [26]. The functional integrity of the neuronal innervation of the heart may be estimated by calculating the storage half-life using C-11-PHEN. A potentially very attractive example of successful translation of a radiotracer from bench to bedside is N-[3-bromo4-(3-[F-18]fluoro-propoxy)-benzyl]-guanidine (LMI1195). This radiotracer was designed using a similar structure as I-123-MIBG, a SPECT tracer for the norepinephrine transporter. I-123-MIBG has been proven to be valuable in many clinical studies, particularly in patients with heart failure, with the aim to identify those subjects who would profit from ICD implantation [27]. Between the first reported use in cells and animals [28] and the first published investigation in humans just lie 3 years [29]. As the image quality is far above I-123MIBG, its clinical availability is of high interest (Fig. 3).
Fig. 3 F-18-LMI1195 as a marker of sympathetic innervation. The rabbit data where created on a fully integrated PET/MRI system in a simultaneous measurement
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Besides the aforementioned agents, there are also radiotracers that allow the assessment of the postsynaptic receptor density. The non-invasive quantification of cardiac βadrenoceptors is of high clinical interest as it is known that numerous pathophysiological conditions (such as hypertension, heart failure, ischemia, or various cardiomyopathies) have an influence on the density of those receptors. Examples of radiotracers that have been used for this purpose are C-11-CGP12177, C-11 carazolol, or F-18 fluorocarazolol [30]. Muscarinic receptors, which are known to play a pivotal role in the regulation of the heart cycle, have also been studied in some studies and one of the most promising radiotracers is C-11 methylquinuclidinylbenzilate (C-11-MQNB) [31]. Other Potential Targets Most of the tracers mentioned above have at least partly been translated to the human use. However, there are still some agents that will have to prove their potential in humans. Neoangiogenesis One tracer that was promising in small animal studies is 18Fgalacto-arginine-glycine-aspartate (RGD). This tracer has high affinity to αvβ3 integrin receptors which are known to be overexpressed on the endothelial surface during neoangiogenesis. Recently, gallium-68-labeled RGD tracers have been developed, e.g., Ga-68-NOTA-RGD [32]. Ga-68 is a radionuclide that is particularly interesting for PET centers without an installed cyclotron as it is produced from commercially available germanium-68 generator system. Apoptosis The most frequently studied tracer for apoptosis is annexin-V. This tracer binds with high specificity to phosphatidylserine, which is overexpressed on apoptotic cells. For radiolabeling of this molecule with positron emitters, both C-11 and Ga-68 have been used. This tracer has recently been investigated for the evaluation of parathyroid hormone treatment in a mouse model of myocardial infarction [33]. While initial results using annexin-V tracers for apoptosis imaging in animals were feasible and also some clinical studies have been conducted, the final transition into human is still pending.
Conclusions Besides an unmet clinical need for non-invasive imaging, several prerequisites are necessary for a successful transition of novel molecular imaging approaches into clinics: technological development, suitable animal models, and development of probes. Nuclear imaging—and particularly PET—offers some
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advantages over other imaging modalities which include the very high sensitivity, a wide armamentarium of probes as well as the ongoing development of new agents, and the good availability of imaging devices. Disadvantages in PET imaging are, however, the relatively low spatial resolution, the ionizing radiation burden, the lack of detailed morphologic information, and the high costs for radionuclide production (either by generator or cyclotron). Some issues have already been resolved by the combination of different imaging modalities resulting in hybrid scanners such as PET/CT or PET/MR. Another hurdle that should not be underestimated are the regulatory burdens—particularly in many countries of the Western societies—that need to be overcome until a promising probe can finally make it into clinics. However, if one makes it to overcome all these stumbling blocks, PET is one of the most promising techniques for translational research nowadays. Compliance with Ethics Guidelines Conflict of Interest C. Rischpler, Anna Paschali, Constantinos Anagnostopoulos, and S.G. Nekolla declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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