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SPECT and PET Imaging of Angiogenesis and Arteriogenesis in Pre-Clinical Models of Myocardial Ischemia and Peripheral Vascular Disease

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SPECT and PET Imaging of Angiogenesis and Arteriogenesis in Pre-Clinical Models of Myocardial Ischemia and Peripheral Vascular Disease Eur J Nucl Med Mol Imaging DOI 10.1007/s00259-016-3480-8 REVIEW ARTICLE SPECT and PET imaging of angiogenesis and arteriogenesis in pre-clinical models of myocardial ischemia and peripheral vascular disease Geert Hendrikx1,4 & Stefan Vöö1 & Matthias Bauwens1,5 & Mark J. Post2,4 & Felix M. Mottaghy1,3 Received: 1 April 2016 /Accepted: 28 July 2016 # The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Conclusion Although angiogenesis is the process which is Purpose The extent of neovascularization determines the clin- best understood, there is no scarcity in theoretical targets for ical outcome of coronary artery disease and other occlusive arteriogenesis imaging. cardiovascular disorders. Monitoring of neovascularization is therefore highly important. This review article will elaborately Keywords Radiotracer imaging . Angiogenesis . discuss preclinical studies aimed at validating new nuclear Arteriogenesis . Myocardial infarction . Peripheral vascular angiogenesis and arteriogenesis tracers. Additionally, we will disease briefly address possible obstacles that should be considered when designing an arteriogenesis radiotracer. Methods A structured medline search was the base of this Introduction review, which gives an overview on different radiopharma- ceuticals that have been evaluated in preclinical models. Molecular imaging enables the study of molecular and cellular Results Neovascularization is a collective term used to indicate processes in vivo [1]. Within this field, several noninvasive different processes such as angiogenesis and arteriogenesis. imaging techniques such as Magnetic Resonance imaging However, while it is assumed that sensitive detection through (MRI), Computed Tomography (CT), Optical Imaging (OI), nuclear imaging will facilitate translation of successful thera- Positron Emission Tomography (PET) and Single Photon peutic interventions in preclinical models to the bedside, we Emission Computed Tomography (SPECT) are distinguished. still lack specific tracers for neovascularization imaging. Most The latter two are the most established techniques for targeting nuclear imaging research to date has focused on angiogenesis, ongoing biochemical processes and are based on the detection leaving nuclear arteriogenesis imaging largely overlooked. of injected radiolabeled probes. While the spatial resolution of MRI and CT is higher, the detection sensitivity of PET and SPECT is within the picomolar or nanomolar range and there- * Felix M. Mottaghy [email protected] fore significantly higher than for MRI and CT [2, 3]. Spatial resolution and detection sensitivity are two performance char- 1 Department of Nuclear Medicine, Maastricht University Medical acteristics that play an important role in molecular imaging Centre (MUMC+), Postbox 5800, 6202 research using SPECT and PET tracers. Clinical gamma cam- AZ Maastricht, The Netherlands eras can provide a tomographic resolution of about 10 mm 2 Department of Physiology, Maastricht University, while preclinical devices currently reach submillimeter reso- Maastricht, The Netherlands lutions using a specialized multipinhole geometry [2, 4]. The 3 Department of Nuclear Medicine, University Hospital, RWTH difference between clinical and preclinical PET devices is Aachen University, Pauwelsstr. 31, Aachen 52072, Germany smaller. While preclinical scanners reach spatial resolutions 4 Cardiovascular Research Institute Maastricht (CARIM), Maastricht of 1–2 mm, clinical scanners operate within the range of 4– University, Maastricht, The Netherlands 6 mm. The application for dedicated small animal SPECT and 5 School of Nutrition and Translational Research in Metabolism PET imaging modalities in preclinical models is highly valu- (NUTRIM), Maastricht University, Maastricht, The Netherlands able, as it has a great scope for noninvasive studying of Eur J Nucl Med Mol Imaging dynamic biological processes at the molecular and cellular important for imaging of neovascularization. Perfusion tracers level [2]. Because of the high societal burden of disease, the are even used as surrogate markers for neovascularization in cardiovascular system is a well-recognized target for molecu- pre-clinical research (BRadiotracer imaging of arteriogenesis^ lar imaging. Longitudinal studies, monitoring cardiac function section). Accordingly, this section serves as a brief introduc- [5], imaging of atherosclerosis [6, 7], tissue viability and per- tion into the uptake mechanisms, kinetics, and application of fusion [8] and neovascularization [9, 10] are among the most the most common SPECT and PET perfusion tracers. studied cardiovascular areas. Molecular imaging of neovascu- Frequently employed perfusion tracers for SPECT are larization has received a significant amount of attention as we Thallium-201 (201Tl), Technetium-99 m (99mTc)-sestamibi, still lack sensitive detection of neovascularization. It is as- 99mTc-tetrofosmin and 99mTc-pyrophosphate, while for PET, sumed that such sensitive detection will facilitate translation Oxygen-15 (15O)-water, N-13 (13N)-ammonia, Rubidium-82 of successful therapeutic interventions in preclinical models to (82Rb) and the more recently developed Fluorine-18 (18F)- the bedside [8, 11]. Neovascularization can be divided in three labeled Flurpiridaz (Lantheus Medical Imaging, distinct processes, vasculogenesis, arteriogenesis and angio- Massachusetts, USA) are the most common perfusion tracers. genesis [12], and its extent determines the clinical outcome of 201Tl is taken up in viable cells via the sodium-potassium coronary artery disease and other occlusive cardiovascular pump as it has properties similar to potassium [17]. However, disorders. Vasculogenesis refers to the in situ formation of while 201Tl has successfully been used in cardiac perfusion blood vessels from circulating endothelial progenitor cells. imaging [18] and in skeletal muscle perfusion imaging in Despite the importance of this process during embryogenesis, PVD patients [19–22], 99mTc-labeled perfusion tracers have its further discussion is beyond the scope of this review. The largely replaced the use of 201Tl. Beside the considerably low- term arteriogenesis describes the enlargement of pre-existing er radiation exposure (6 vs. 28 millisievert) 99mTc-labeled arteriolar anastomoses into large collaterals in response to en- tracers offer more advantages compared to 201Tl, the most hanced fluid shear stress [13]. Angiogenesis is an ischemia essential being the shorter half-life (6 h for 99mTc compared driven process that represents the sprouting of new capillaries to 73 h for 201Tl), allowing for injection of higher doses, in from existing microvasculature [9]. combination with the higher energy level at which 99mTc emits Arteriogenesis is the most important mechanism in the func- gamma rays [140 k electronvolt (keV) compared to 78 keV for tional replacement of an occluded artery in peripheral vascular 201Tl], which results in less scatter and attenuation. Together, disease (PVD) [13, 14], but the enlargement of coronary col- these advantages culminate in improved imaging [23]. lateral arteries in obstructive coronary artery disease is also well One 99mTc-labeled compound in particular, 99mTc- described [15]. Angiogenesis is associated with postinfarct re- sestamibi, is omnipresent in clinical cardiology [24] and has modeling and has important implications for the prognosis fol- also been incorporated in several studies examining lower- lowing myocardial infarction (MI) [16], whereas its role in extremity perfusion in PVD [25–27]. 99mTc-sestamibi is a li- perfusion recovery in PVD is of less importance [13]. In this pophilic, cationic complex of six isonitriles [23]. Like 201Tl, review, we will focus on SPECT- and PET-based neovascular- uptake of 99mTc-sestamibi after intravenous injection is pro- ization studies in the context of MI and peripheral vascular portional to blood flow [28]. Cellular uptake and retention of disease (PVD). As will become apparent from this review, ex- 99mTc-sestamibi are dependent on mitochondrial and plasma tensive research has been conducted concerning radiotracer im- membrane potentials [29–31]. After uptake, the compound aging of angiogenesis, while arteriogenesis radiotracer imaging resides in myocardial cells after initial extraction and demon- is scarce and largely overlooked. Despite large parts of the strates minimal delayed redistribution [32–34]. In a case re- pathways involved in arteriogenesis being unraveled, radio- port, the merit of clinical application of 99mTc-sestamibi over tracers specifically targeting this multifactorial process are yet Doppler ultrasound in PVD patients has already been reported to be developed. Alluding to the inferior amount of work being on the basis of improved sensitivity in detecting differences in published on radiotracer imaging of arteriogenesis, we will detecting differences of resting perfusion between the lower briefly discuss the possible hurdles which have to be overcome extremities [35]. 99mTc-tetrofosmin is an alternative lipophilic in order to develop a nuclear arteriogenesis tracer. cationic complex with comparable uptake characteristics and similar widespread use in myocardial perfusion imaging [24]. However, the hepatobiliary clearance of 99mTc-tetrofosmin is Perfusion tracers in neovascularization research reported to be slightly faster than for 99mTc-sestamibi [23]. Recently, Stacy et al. showed preliminary data and indicated Although perfusion radiotracers do
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