What Is a Sestamibi Scan and How Does It Work?

A sestamibi scan is a nuclear medicine imaging test in which a small amount of a radioactive tracer, technetium-99m sestamibi, is injected into a vein so that a specialized camera can photograph how the tracer distributes through specific organs. It is most commonly used for two purposes: locating overactive parathyroid glands and evaluating blood flow to the heart muscle. The tracer works by accumulating inside cells that are metabolically active, which makes abnormal tissue light up on the images relative to the surrounding normal tissue.

How the Tracer Gets Inside Cells

Technetium-99m sestamibi is a fat-soluble molecule that carries a positive charge. Once injected into the bloodstream, it crosses cell membranes and is drawn into mitochondria, the tiny energy-producing structures inside cells. Tissues that are especially rich in mitochondria or have high metabolic activity take up more of the tracer and hold onto it longer. Research on human parathyroid tissue has confirmed that mitochondrial activity is the primary driver of sestamibi uptake: when scientists added a chemical that shuts down mitochondrial function, roughly 85 percent of the tracer was released from the mitochondrial compartment.¹

A second factor involves a protein called P-glycoprotein, which acts as a pump that pushes the tracer back out of cells. Normal parathyroid glands have relatively high levels of this pump, so the tracer washes out quickly. Abnormal parathyroid tissue, such as an adenoma, has much lower levels of P-glycoprotein, meaning the tracer stays trapped longer.² This combination of eager uptake and slow washout is the entire basis for making abnormal tissue visible on the scan.

Finding Overactive Parathyroid Glands

The parathyroid glands are four pea-sized glands behind the thyroid in the neck. When one of them develops a benign growth (an adenoma), it overproduces parathyroid hormone and causes high blood calcium. Surgery to remove the offending gland is the standard treatment, but the surgeon needs to know which gland, and exactly where it sits, before going in. That is where the sestamibi scan earns most of its clinical reputation.

After the tracer is injected, images are taken at two time points. In the early images, both the thyroid and any abnormal parathyroid tissue will show uptake. By the later images, the thyroid has washed the tracer out, but the adenoma keeps glowing. This “double-phase” approach was described in early studies that correctly detected and localized about 90 percent of parathyroid adenomas.³ Another common approach uses a subtraction technique: sestamibi is given alongside a second radiotracer that is taken up only by the thyroid. A computer then subtracts the thyroid-only image from the combined image, leaving just the parathyroid tissue behind.⁴

The scan is also useful for detecting glands that have migrated to unusual locations during embryonic development. Sometimes a parathyroid gland ends up deep in the chest rather than in the neck, and a standard neck ultrasound would never find it. Because a sestamibi scan covers a wide field from the jaw down to the upper chest, it can catch these ectopic glands.⁵ Reported sensitivity ranges widely, from about 60 to 90 percent, depending on the imaging protocol, the size of the adenoma, and whether a patient has a single enlarged gland or multiple abnormal glands.²

Evaluating Blood Flow to the Heart

The other major use of sestamibi is in cardiac stress testing. Here the tracer serves as a blood-flow marker: wherever blood reaches the heart muscle, sestamibi follows. If a coronary artery is significantly narrowed, the portion of heart muscle it feeds receives less tracer during stress, and the images show a “cold spot” in that region.

A typical cardiac sestamibi study involves two sets of images. One set is taken at rest, and another is taken after the heart has been stressed, either by exercise on a treadmill or by a drug that mimics the effect of exercise. Comparing the two reveals whether any part of the heart is starved for blood only when the heart is working hard, a hallmark of coronary artery disease. A systematic review comparing sestamibi SPECT to other cardiac imaging found a mean sensitivity of about 84 percent and specificity of about 75 percent for detecting coronary artery disease.⁶ In elderly patients over 80, one study reported even higher sensitivity, around 95 percent, with acceptable specificity regardless of whether the patient exercised or received a drug stressor.⁷

The test has also been studied specifically in women, for whom standard treadmill testing without imaging is less reliable. In women undergoing adenosine sestamibi SPECT, a severely abnormal scan showed a sensitivity of 91 percent and specificity of 70 percent for identifying high-risk coronary disease.⁸ One property that makes sestamibi convenient for cardiology is that it does not redistribute after injection. Unlike older tracers, the image you get an hour later still reflects blood flow at the moment of injection, giving technologists flexibility in scheduling the camera time.⁹

What Happens During the Procedure

Preparing the tracer itself is a small production. A technologist elutes a generator (a shielded device that continuously produces technetium-99m from its parent isotope, molybdenum-99) using saline to collect sodium pertechnetate. This solution is then added to a commercially available cold kit vial and heated on a 120°C heat block to complete the chemical reaction that forms sestamibi.¹⁰ After quality checks, the dose is drawn up and injected into a vein in your arm.

For a parathyroid study, you typically lie on a table under a gamma camera while images are taken at an early time point (around 15 to 20 minutes after injection) and again at a delayed time point (two or more hours later). Some protocols add SPECT/CT, which combines the nuclear medicine images with a low-dose CT scan to give three-dimensional localization. The whole visit can stretch over several hours, though you spend only a fraction of that time on the camera table. For a cardiac study, the protocol depends on whether you exercise or receive a pharmacologic stressor, and often involves two separate injections (rest and stress), potentially spanning two visits or one long session.

Breast Cancer Screening and Other Oncology Uses

Sestamibi is not limited to parathyroids and hearts. Because cancer cells tend to have high metabolic activity and altered P-glycoprotein expression, the tracer accumulates in many tumors. The most developed application outside cardiology and parathyroid imaging is molecular breast imaging (MBI), a technique that uses dedicated small gamma cameras positioned to compress the breast while sestamibi circulates through it. These cameras use semiconductor detectors made of cadmium zinc telluride, which convert gamma rays directly into electronic signals for sharper images.¹¹

MBI has gained attention as a supplemental screening tool for women with dense breast tissue, in whom standard mammography can miss cancers because the dense tissue masks tumors on the X-ray image. MBI can detect mammographically occult cancers in this population.¹² Technical advances over the past decade have allowed lower-dose, higher-resolution imaging and even biopsy capability, making MBI increasingly practical for everyday clinical use.¹³

Sestamibi SPECT/CT has also found a role in characterizing indeterminate kidney masses found on other imaging, offering a cost-effective way to help distinguish benign from potentially malignant lesions without resorting to biopsy.¹⁴

Radiation Dose and Safety

Any nuclear medicine test involves some radiation exposure, and patients often want to know how much. For a sestamibi scan used in parathyroid localization, the effective dose is in the range of about 3 to 6 mSv. One comparative study measured a mean dose of about 3.3 mSv for sestamibi scintigraphy versus roughly 5.6 mSv for a dynamic parathyroid CT scan.¹⁵ For context, average background radiation in the United States is about 3 mSv per year, and exposures below 15 mSv are generally considered low risk. A separate study evaluating the cancer risk from parathyroid imaging found the highest attributable lifetime risk after sestamibi was for colon cancer, at about 0.06 percent, a very small number.¹⁶

Cardiac studies typically use higher tracer doses because the heart is deeper in the body and more counts are needed for good image quality, so the effective dose is higher than in a parathyroid scan. Nonetheless, modern protocols have pushed doses down significantly compared with older techniques, especially with newer camera hardware. Pregnant women are generally advised to avoid the test unless it is absolutely necessary, and breastfeeding mothers may need to pump and discard milk for a period after the injection.

False Positives, False Negatives, and the Balanced Ischemia Problem

No imaging test is perfect, and knowing the pitfalls of a sestamibi scan helps you interpret the results. On the parathyroid side, thyroid nodules, thyroid inflammation, and even enlarged lymph nodes can retain the tracer and mimic a parathyroid adenoma, producing a false positive. A more mundane problem: if the tracer is injected and some of it pools in the vein rather than entering the bloodstream cleanly, the pooled tracer can masquerade as an ectopic parathyroid gland. One simple fix is to inject the tracer in the arm opposite the side of concern.¹⁷ False negatives are more common when the adenoma is small, particularly those weighing less than about 600 to 800 milligrams.²

On the cardiac side, a particularly tricky pitfall is “balanced ischemia.” If all three major coronary arteries are equally and severely narrowed, the entire heart muscle gets reduced blood flow during stress, but because the camera compares different regions to each other, everything looks uniformly diminished rather than focally abnormal. The result can be a normal-appearing scan in someone who actually has severe disease. A case report documented exactly this scenario: a sestamibi stress test was read as normal, but advanced CT-based fractional flow reserve analysis revealed significant disease in multiple vessels.¹⁸ Balanced ischemia is uncommon but worth knowing about because it tends to occur in exactly the patients who are at highest risk.

How Sestamibi SPECT Stacks Up Against Other Imaging

Doctors today have several imaging options for both parathyroid localization and cardiac perfusion, and the question of how sestamibi compares comes up often.

For parathyroid localization, four-dimensional CT (4D-CT) has become a strong competitor. A large study found that 4D-CT had higher sensitivity than sestamibi SPECT/CT, around 79 percent versus 58 percent overall, with an even larger gap in patients who had multiple abnormal glands.¹⁹ However, a more recent study reported similar overall accuracy for the two modalities, with sestamibi SPECT/CT reaching about 92 percent accuracy, and found that combining both tests did not significantly outperform sestamibi SPECT/CT alone.²⁰ The discrepancy likely reflects differences in the patient populations studied and the specific imaging protocols used. In practice, many surgical centers use both tests together so that one can compensate for the other’s blind spots.

For cardiac imaging, PET scanning with rubidium-82 is often considered the gold standard. Interestingly, a systematic review found that sestamibi SPECT actually had a slightly higher mean sensitivity for detecting coronary disease (about 84 percent versus 81 percent), though PET had better specificity (81 percent versus 75 percent).⁶ PET has practical advantages, including faster imaging and the ability to quantify blood flow in absolute terms, but it requires an on-site rubidium generator and is considerably more expensive. Sestamibi SPECT remains the workhorse at most hospitals because of its availability and lower cost. Newer solid-state detector SPECT cameras are narrowing the gap, now enabling dynamic imaging that can calculate absolute blood flow, a capability that was previously exclusive to PET.²¹

Why It Replaced Thallium-201

Before sestamibi came along, the main radiotracer for cardiac perfusion imaging was thallium-201. Thallium works well enough, and it was a foundational tool in nuclear cardiology throughout the 1970s and 1980s. But it has a low photon energy, which produces grainier images, and a long physical half-life, which translates to a higher radiation dose to the patient. Reinjection protocols used to improve image quality only made the dose problem worse.⁹ Technetium-99m emits higher-energy photons that are better suited to gamma camera detection, has a six-hour half-life that keeps radiation exposure in check, and can be produced on-site from a generator rather than shipped from a cyclotron. The combination of better image quality, lower dose, and more practical logistics made sestamibi the dominant cardiac perfusion tracer worldwide.

Emerging Camera and Software Advances

The tracer itself has not changed since its approval, but the hardware and software used to image it have improved dramatically. Traditional gamma cameras used sodium iodide crystals to detect photons, but newer cameras use cadmium zinc telluride (CZT) semiconductor detectors. These solid-state detectors are more sensitive, meaning they can produce the same image quality with a lower injected dose or produce better images with the same dose. One remaining limitation of SPECT, whether conventional or CZT, is that soft tissue like the diaphragm can absorb photons unevenly and create artifacts, particularly in the territory supplied by the right coronary artery. A recent study tested a deep-learning approach that generates a virtual attenuation correction map from the SPECT data itself, eliminating the need for a separate CT scan purely for correction. The technique produced more uniform tracer distribution across all coronary territories, reducing the artifact that had long been a known annoyance with standard correction methods.²²

Meanwhile, an entirely separate line of research uses sestamibi as a research tool to study drug-transporter function in the body. Because P-glycoprotein pumps sestamibi out of cells, researchers can track the tracer to measure how active this pump is in different organs. In animal models, sestamibi outperformed several PET tracers at detecting reduced P-glycoprotein activity in the kidneys and liver.²³ This matters for drug development, because P-glycoprotein influences how many medications are absorbed and eliminated. Sestamibi may eventually serve as a clinical tool for predicting whether a patient’s drug-transporter profile will affect how they process certain medications, an application that stretches far beyond anything the tracer’s original developers imagined.