Radiopharmaceuticals for clinical SPECT and PET and imaging protocols

KEY POINTS

A key physiologic attribute that defines the quality of a MPI agent is defined by the relationship between the tracer uptake and MBF. A linear relationship maximizes the sensitivity of the tracer to identify flow-limiting coronary artery stenosis.
Cardiac SPECT perfusion tracers include ²⁰¹ Tl and the ^99m Tc-labeled tracers, tetrofosmin and sestamibi.
²⁰¹ Tl has better extraction than ^99m Tc-labeled tracers at high blood flow rates, but its lower photon energy and higher radiation dose make it less ideal for clinical SPECT imaging.
^99m Tc-labeled tracers’ photon energies (140 keV) are ideal for clinical SPECT systems. Their more favorable organ dosimetry allows for higher injected doses, resulting in less attenuation artifacts and improved image quality.
Clinical radiotracers for PET MPI include ⁸² Rb and ¹³ N-ammonia.
⁸² Rb has a very short half-life and can only be used with pharmacologic stress testing.
¹³ N-ammonia can be used with pharmacologic- or exercise-stress testing.
New PET tracers for myocardial perfusion and delivery systems may offer further advantages for PET MPI in the near future.
MPI protocols should be tailored based on the patient’s history and imaging equipment to maximize image quality while minimizing radiation exposure.
Stress-only imaging is one of the most effective protocols for reducing radiation exposure and is best suited for patients without a history of CAD.
^99m Tc-PYP is an effective radiotracer for the detection of ATTR amyloid cardiomyopathy.
¹²³ I-mIBG is a norepinephrine analog that is approved for the imaging of cardiac sympathetic nerve function in patients with heart failure.

Introduction

Radioactive tracers for cardiac imaging have evolved significantly since the 1970s when Zaret and Strauss used potassium (K)-43 to noninvasively assess myocardial perfusion after treadmill exercise. Although development of new radioactive tracers for cardiac imaging was relatively static from the mid-1990s on, there have been a number of recent advancements in the development and delivery of radioactive tracers that bring new options to modern nuclear cardiology.

The most common application of radioactive tracers in cardiac imaging is for the assessment of myocardial perfusion. A key concept to optimally use and interpret radionuclide perfusion images is the understanding of the ideal physiologic characteristics of radioactive tracers for the assessment of myocardial tissue perfusion. These characteristics have been well described and combine five key properties:

1.
High myocardial uptake;
2.
High first-pass extraction with a linear relationship between myocardial radiotracer uptake and myocardial blood flow (MBF);
3.
High target-to-background ratio to avoid imaging contamination from adjacent organs;
4.
Ability to quantify MBF; and
5.
Transport of the radiotracer must track the physiologic effects of altered blood flow.

As shown in Fig. 4.1 , current myocardial perfusion radiotracers have varying degrees of nonlinear relationships between their tissue uptake relative to actual MBF. The lack of linearity between myocardial uptake and blood flow (so-called “roll off”), especially at high flow rates, has a direct impact on the degree of heterogeneity in radiotracer tissue retention, which, in turn, affects the sensitivity of the test for uncovering varying degrees of coronary stenoses. For example, ^99m technetium-labeled myocardial perfusion radiotracers show a marked roll off of uptake at higher blood flow rates that explains, in part, their relatively lower sensitivity for evaluating the functional significance of coronary stenosis of intermediate severity (50% to 70%).

Fig. 4.1, Myocardial tracer uptake relative to blood flow.

Despite nuclear cardiology’s history and foundation in myocardial perfusion imaging, the field is rapidly evolving to include other relevant imaging targets in clinical medicine, including cardiac sympathetic innervation and amyloidosis, which are changing disease management. Novel radioactive tracers for myocardial perfusion imaging with positron emission tomography (PET) are currently in clinical trials. In addition, there are advances in production and delivery systems of PET perfusion radiotracers that are improving clinical access to cardiac PET imaging.

This chapter will review commonly used radioactive tracers for single photon emission computed tomography (SPECT) and PET imaging of the heart, primarily for the assessment of perfusion but also for imaging of nonperfusion targets.

Current radiotracers for cardiac imaging

SPECT radiotracers

Radionuclide myocardial perfusion imaging was developed in the 1970s and included the rapid clinical development of ²⁰¹ thallium ( ²⁰¹ Tl) with its U.S. Food and Drug Administration (FDA) approval in 1977 as a myocardial perfusion tracer. Although it possesses good physiologic properties for tracking MBF, ²⁰¹ Tl has radiophysical properties that limit its use, including high radiation exposure that limits injected doses and low photon energy, both of which make imaging challenging, especially in obese patients. These limitations led to the development and commercialization of ^99m technetium ( ^99m Tc)-labeled lipophilic cations, specifically sestamibi (FDA-approved in 1990) and tetrofosmin (FDA-approved in 1996). Despite the suboptimal relationship between their myocardial tracer uptake and blood flow, the ^99m Tc-labeled tracers have earned a dominant place in modern nuclear cardiology practice. In addition to the myocardial perfusion imaging (MPI) tracers, ^99m Tc-pyrophosphate (PYP) and ¹²³ I-meta-iodobenzylguanidine ( ¹²³ I-mIBG) are commonly used for cardiovascular molecular imaging of transthyretin (ATTR) cardiac amyloidosis and sympathetic innervation, respectively. An overview of radiotracers for cardiac SPECT is summarized in Table 4.1 .

TABLE 4.1

Overview of Cardiac Single Photon Emission Computed Tomography Radiotracers

Tracer	Physical Half-life (in hours)	Primary Photon Energy	Source	Uptake	Myocardial Clearance	Redistribution	Maximum Extraction Fraction
²⁰¹ Thallium	73	68–82 keV	Cyclotron	Active; Na/K ATPase	50% at 6 hours	Yes	85%
^99m Technetium-sestamibi	6.02	140 keV	Generator	Passive; mitochondrial membrane potential	Minimal	Minimal	55%–65%
^99m Technetium-tetrofosmin	6.02	140 keV	Generator	Passive; mitochondrial membrane potential	Minimal	Minimal	50%–55%
^99m Technectiumpyrophosphate	6.02	140 keV	Generator	Extracellular calcium	Minimal	None	NA
¹²³ Iodine	13.2	159 keV	Cyclotron	Active	Minimal	None	NA

ATP, Adenosine triphosphate; NA , not available.

²⁰¹ Thallium

²⁰¹ Tl is produced in a cyclotron from the proton-bombardment of nonradioactive ²⁰³ Tl, lead, and/or bismuth and decays via a 68- to 82-keV mercury characteristic x-ray emission. ²⁰¹ Tl can also be produced from ²⁰¹ lead (half-life of 9.3 hours) by a generator-based method. Because of its long half-life (73 hours), ²⁰¹ Tl is usually transported from the cyclotron to the end user.

Mechanism of retention and property of redistribution

²⁰¹ Tl is a potassium analog whose initial cellular uptake is facilitated by the sarcolemmal adenosine triphosphate (ATP)-requiring Na+/K+ ATPase. Like most perfusion tracers, initial ²⁰¹ Tl uptake is proportional to MBF at low/intermediate flow rates with “roll off” and loss of proportionality to flow at higher flow rates (see Fig. 4.1 ). Myocardial first-pass extraction of ²⁰¹ Tl is superior to that of the ^99m Tc-labeled agents, meaning smaller differences in MBF are required to visualize differential tracer uptake relative to flow and potentially increasing sensitivity for less severe ischemia. In addition, ²⁰¹ Tl exhibits biexponential clearance, also known as redistribution , which allows for delayed imaging to evaluate for chronically hypoperfused, but still viable, myocardium. In simplistic terms, normally perfused regions of the myocardium have a faster rate of washout than ischemic regions, allowing for the use of late (4 or 24 hours postinjection) redistribution images to define areas of myocardial hibernation and/or viability. Limitations of ²⁰¹ Tl include its long half-life, which leads to high effective radiation exposure and limits the dose that may be given compared with other perfusion radiotracers. In addition, the relatively low photon energy of ²⁰¹ Tl makes it less ideal for imaging patients where nonuniform attenuation is present (e.g., obesity, large breast, diaphragmatic attenuation).

^99m Technetium-based radiotracers

^99m Tc can be produced on site using a commercially available ⁹⁹ molybdenum ( ⁹⁹ Mo) generator, a fission reaction product of ²³⁵ uranium ( ²³⁵ U) produced in a nuclear reactor. ⁹⁹ Mo lybdenum slowly undergoes β- decay (half-life of 66 hours) with 87.5% of the decay product being ^99m Tc. The “m” superscript refers to a metastable excited state that is an intermediate between the excited and stable nuclear states. ^99m Technetium produces a 140-keV gamma emission by isomeric transition to produce the stable daughter, ⁹⁹ technetium. The generator prepared at the radiopharmaceutical manufacturer includes ⁹⁹ Mo tightly bound to an alumina (Al ₂ O ₃ ) column. ^99m Tc can be eluted (“milked”) from the column with normal saline as ^99m Tc-pertechnetate into a collection vial. ^99m Tc can then be chemically linked to sestamibi or tetrofosmin using commercial kits or acquired through commercial radiopharmacies in prebound unit doses.

In recent years, significant issues have arisen with worldwide molybdenum-99m supply. Starting in 2007, aging research reactors across the world that are the major producers of ⁹⁹ Mo have experienced frequent shutdowns, causing critical supply chain disturbances in 2009 and 2010. This led to worldwide shortages of ⁹⁹ Mo and, consequently, ^99m Tc, prompting the need to seek alternative imaging agents for radionuclide perfusion imaging (e.g., ⁸² rubidium [ ⁸² Rb] and ¹³ N-ammonia). Current international multigovernmental and industry approaches are working to create a sustainable ⁹⁹ Mo supply chain for the coming decades.

^99m Technetium has a 6.02-hour half-life, permitting higher doses to be used with lower radiation exposure compared with ²⁰¹ Tl, which reduces photon scatter and improves image quality, particularly when soft tissue attenuation is present. Because of the superior image quality afforded by the higher energy emission (140 keV for ^99m Tc vs. 60 to 80 keV for ²⁰¹ Tl) and the lower effective radiation dose, the ^99m Tc agents have largely supplanted ²⁰¹ Tl for routine evaluation of myocardial perfusion with SPECT.

Mechanism of retention

^99m Technetium-labeled sestamibi and tetrofosmin are lipophilic cations that exhibit MBF–dependent first-pass extraction and are retained in proportion to mitochondrial membrane potential. Both are rapidly cleared from blood early (within 10 minutes) after intravenous (IV) injection and are predominately cleared by hepatobiliary metabolism, which can cause significant uptake adjacent to the heart in many patients and cause significant artifacts, which reduce sensitivity and specificity, as discussed in greater detail in Chapter 5 . ^99m Technetium-tetrofosmin has a shorter biologic half-life but greater heart-to-liver uptake ratio compared with sestamibi. ^,

^99m Technetium-Pyrophosphate

^99m Technetium-PYP was originally developed and approved for bone scintigraphy and historically used to detect acute myocardial infarction but has recently been repurposed as an imaging agent for cardiac ATTR amyloidosis (see discussion in Chapter 24 ). PYP is supplied as a kit that includes sodium PYP and stannous chloride reconstituted with raw ^99m Tc sodium pertechnetate. The mechanism of retention of PYP appears to rely on local increases in extracellular calcium common in both acute myocardial infarction and ATTR amyloid deposits.

¹²³ I-Meta-Iodobenzylguanidine

Increased myocardial sympathetic activity is present in heart failure and is an independent predictor of prognosis and poor outcomes, including sudden cardiac death independent of left ventricular (LV) function. Myocardial sympathetic innervation can be assessed using ¹²³ I-meta-iodobenzylguanidine ( ¹²³ I-mIBG) cardiac imaging. The ratio of heart to mediastinal ¹²³ I-mIBG uptake (H:M ratio) has been demonstrated to improve risk prediction in validated clinical variable-based models as a low myocardial ¹²³ I-mIBG uptake (and low H:M ratio) identifies high-risk patients and a H:M ratio greater than 1.6 imparts a low risk. ¹²³ I-mIBG is FDA-approved for the assessment of myocardial sympathetic innervation and mortality risk with patients with New York Heart Association Class II/III heart failure and an LV ejection fraction equal to or less than 35%. Please see detailed discussion on the application of cardiac sympathetic nerve imaging in Chapter 21 .

Production

¹²³ Iodine is produced in a cyclotron and decays via electron capture to ¹²³ Te, producing a 159-keV photon. ¹²³ Imeta-iodobenzylguanidine is compounded as iobenguane sulfate at a radiopharmacy.

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