68 Ga-DOTA chelate, a novel imaging agent for assessment of myocardial perfusion and infarction detection in a rodent model

by Anu Autio,

Turku PET Centre, University of Turku

Heart Center, Turku University Hospital and University of Turku

Turku Center for Disease Modeling, University of Turku

In this JNC issue, Dr. Autio and his colleagues introduce 68Ga-DOTA chelate as new tracer for the delineation of myocardial perfusion as well as extracellular space in a rodent infarct model. This application has most likely been triggered by the fact that gadolinium chelates are widely being used as contrast agent in magnetic resonance imaging (MRI). In cardiac MRI (CMRI), the use of Gd-chelates represents an established technology for the work-up of patients with coronary artery disease. Quite interestingly, this class of MR contrast agents was modeled in the 1980s after a tracer principle in nuclear medicine—99mTc-DTPA.1

The advantages of MRI in terms of high spatial resolution and lack of ionizing radiation have supported the clinical application of Gd-chelates for the imaging of myocardial perfusion, the delineation of myocardial scar as well as—in more general terms—for the detection of alterations in extracellular volume.2,3,4 However, there have been questions about the possible toxicity of these contrast agents as gadolinium deposits were found in brain tissue.5 Nevertheless, the technology remains a standard procedure in many cardiovascular imaging centers. Based on this positive experience, it is not surprising that using 68Ga-labelled chelates in combination with dynamic PET acquisition allows a replication of data established in the MR community. The sophisticated first-pass analysis established at the laboratory of the Turku investigators, mainly using 15O-water as the PET tracer, allows an almost automatic quantitative analysis yielding absolute measurements of myocardial perfusion as shown in many publications.6 The group at the University of Turku has already demonstrated that PET 15O-water studies in the normal flow range correlate with the perfusion results obtained after the intravenous bolus injection of 68Ga-DOTA.7

The paper by Dr. Autio et al raises an important question: What are the relative advantages of PET vs MR imaging for extracting biological information such as myocardial perfusion, extracellular space and myocardial infarct extension? For the clinical work-up of patients with suspected coronary artery disease the need for an accurate and robust assessment of myocardial perfusion and coronary flow reserve has been recognized for decades.8 Currently, the most commonly used PET tracer is rubidium-82 (82Rb) because it is generator-used and allows rapid evaluation of rest and stress perfusion due to its short physical half-life of 76 seconds.9 In the scientific community, 13N-ammonia has gained acceptance since it has a high myocardial extraction coupled with a suitable physical half-life of 10 minutes to provide excellent image quality due to the high-tracer retention.10 The drawback of 13N-ammonia is the need of an onsite cyclotron, which limits the use to primarily academic institutions. The same applies to 15O-water, which represents a freely diffusible used for cerebral and myocardial perfusion measurements.

Many publications have indicated that with both 15O-water and 13N-ammonia global as well as regional myocardial blood flow can be well quantified. The non-invasive delineation of coronary reserve has been advocated not only as diagnostic but also prognostic tool.11,12 With the advance of multimodal imaging using PET/CT systems, the combination of both tracers with coronary angiography provides a very attractive but costly tool for the functional and anatomic assessment of regional coronary artery disease.13,14

68Ga DOTA is introduced as tracer for both perfusion and ECV. To apply one tracer providing not only information on perfusion but also on tissue characterization is a promising approach. The authors used 11C-acetate as reference tracer for the estimation of perfusion. 11C-acetate is well extracted by the myocardium but rapidly metabolized by TCA cycle as a function of myocardial oxygen consumption.15 The relatively high first-pass extraction of 11C-acetate allows flow estimates, while fitting of myocardial time activity curves yields estimates of oxidative metabolism.16,17 Nevertheless, such combination provides an attractive research tool to define the integrity of myocardial perfusion and metabolic performance. Together with hemodynamic estimates of cardiac work, several studies have attempted to delineate the cardiac efficiency as marker of overall cardiac performance.18 However, this sophisticated imaging approach has never gained wide clinical acceptance in the management of patients with heart failure primarily due to the challenging imaging technology required for clinical work-up of such patients.1968Ga DOTA does not provide metabolic data, but myocardial tracer retention reflects extracellular space (ECV). This differential tracer kinetics can be exploited to quantitatively assess ECV in similar fashion as done with Gd-chelates by MRI. ECV estimates provide information on infarct extension (late enchancement) and myocardial fibrosis.20 No direct comparison to MR data in the rodent model is provided in the paper by Dr. Autio et al. As shown in their Figure 2a, the time activity curves indicate very little differences in retention, which may limit the infarct extension measurements with 68Ga DOTA in the clinical setting.

The introduction of PET/MR made it possible to compare both imaging modalities in the same patients under identical physiologic conditions.21 Expanding on earlier work, our group indicated recently that myocardial blood flow measurements provided by 13N-ammonia PET and Gd-chelate MR correlate very closely when using a suitable modelling approach.21,22 However, there are distinct differences in the imaging characteristics of both methodologies. PET excels by its high sensitivity but limited spatial resolution as compared to MRI. In addition, the direct comparison of 13N-ammonia kinetics and gadolinium chelate kinetics also demonstrate the difference in contrast kinetics: With the high first-pass extraction of 13N-ammonia myocardial cells and the high sensitivity of PET, excellent imaging quality can be achieved with a relatively small amount of injected tracer activity. A number of tracer kinetic models have been validated indicating that this technology provides robust qualitative, semi-quantitative and quantitative information in many settings of clinical cardiology.23 The kinetics measured simultaneously for Gd-DTPA as shown in Figure 1 indicates that the basic behavior of 13N-ammonia and Gd-chelates are quite different because gadolinium chelates never enter a myocardial cell but are restricted to the plasma volume and the interstitial space. Therefore, the imaging signal is very transient and requires challenging modelling with relatively low signal to noise ratio to extract quantitative information. However, several groups have demonstrated that robust, global and regional blood flow measurements can be obtained in normal volunteers as well as in patients with coronary artery disease.24 The direct comparison of PET and MR highlights the relative strength of each modality. The robust flow visualization and semi-quantitative assessment favors PET as useful tool for “staging” CAD, especially by PET/CTA.14 The high spatial resolution and accurate estimate of infarct size supports the use of MRI. The drawback of MR technology for cardiac imaging currently is the lack of robust and diagnostic coronary angiography.25

Figure 1
figure 1

Time and signal activity curves from a near simultaneous tracer and contrast media injection in a human using a PET/MR system. The red dots and lines represent the arterial input function from a volume of interest (VOI) in the left ventricle, the blue dots and lines are generates from VOIs in the LV myocardium. Note the drastic difference in the tissue curves which reflects the differences in the volume of distribution. Whereas NH3 can distribute to the cell, Gd-chelates are limited to the plasma volume and interstitial space

Full size image

Based on the existing data, there seems to be little need for adding a new PET tracer approach based on the positive experience with Gd-DTPA in the MR community. 68Ga DOTA offers inferior tracer kinetics in the myocardium as compared to the available PET approaches. In addition, there is a number of imaging approaches characterizing infarcted myocardium.26 Since tissue viability has been an issue in patients with recent infarction, the advantage of metabolic tracers as compared to delineation of scar tissue has been addressed by several studies.27 More recently, the emphasis of PET imaging has focused on the identification of inflammation associated with acute ischemic injury.28 With the adjunct of new molecular imaging probes not only the extent of scar but also the “healing” of acutely infarcted myocardium can be followed by a variety of interesting new tracer approaches. However, these exciting new signals have to prove the clinical value in the future.29 It is foreseen that some of these new molecular tracers will be able to target the inflammatory reaction to myocardial infarction and thus provide guidance in possible therapeutic interventions to limit the inflammatory process and, therefore, improve the healing process of the ischemic injury.

In summary, this paper demonstrates that 68Ga DOTA can indeed be used as a radiotracer in a similar fashion as Gd-chelates in cardiac MR imaging. However, in difference to CMRI where it is the only valid option, there seems to be no urgent clinical need for the nuclear cardiology community to translate and validate this tracer approach in nuclear cardiology. The relative strength of PET vs MR favors the use of tracers targeting biological processes associated with ischemic injury, which, however, need further validation as important tools for managing patients with CAD.