SEPTEMBER 2003

SPECT rides first wave of clinical MI applications

Protocols capitalize on surface receptor targeting strategies

By: James Brice

SPECT may not rank with FDG-PET, PET/CT, and the other sexy modalities associated with molecular imaging, but it provides radiologists and nuclear medicine physicians with a practical molecular imaging method that can be applied now, as well as experimental techniques that will influence clinical practice in the future.

SPECT offers opportunities to pair long-lived radioisotopes with low-molecular-weight agents that target cell receptors, said Dr. Richard Wahl, a professor of radiology at Johns Hopkins University. Indium-111- and technetium-99m-labeled peptides that bind to somatostatin receptors have been added to the SPECT armamentarium. Iodine-123 and I-131 are frequently paired with molecular nuclear agents.

Because of the relatively long half-lifes of gamma-emitting radioisotopes, SPECT tends to be easier to work with than PET agents, but PET produces much higher resolution. Only a small proportion of the gamma rays emanating from the patient are detected with SPECT because of the need for collimation, which greatly limits its sensitivity, said Dr. James Thrall, radiologist-in-chief at Massachusetts General Hospital. Radiation scattering reduces spatial resolution, as it is not possible to precisely locate the origin of the scattered photons from the body, he said in an address at the 2003 Molecular Imaging Conference of the American College of Radiology-American Society for Therapeutic Radiology and Oncology, held in May.

SPECT is generally not in the same league as PET for cancer imaging. The sensitivity of PET for staging lung cancer in the mediastinum is 76% to 100%, according to various studies. In comparison, the sensitivity of SPECT for this role is 43% to 75%. PET holds an edge over SPECT for imaging colon and head and neck cancers.

But the value of SPECT should not be underestimated. It is diagnostically powerful and versatile, despite its alleged second-class status. Its molecular imaging capabilities include:

- uncovering, staging, and monitoring numerous cancers;

- examining deep venous thrombosis;

- measuring multidrug resistance to chemotherapy;

- imaging angiogenesis and apoptosis for early diagnoses and measures of therapeutic response; and

- diagnosing and evaluating Parkinson's disease and other neurodegenerative conditions.

SPECT instrumentation design is keeping pace. Improved acquisition electronics and software have been designed with molecular protocols in mind. Software from Philips Medical Systems, for example, facilitates data acquisition from several isotopes simultaneously, according to Josh Gurewitz, vice president of marketing. The data may then be channeled to up to 16 energy windows for processing and display using individualized matrix, zoom, and stop criteria.

Such versatility is aiding molecular protocol development, Gurewitz said. It may lead to efficient clinical approaches in which the uptake patterns of thallium-201 and Tc-99m Apomate in the myocardium, for example, are acquired simultaneously, processed, and displayed. A gated SPECT window can be used to capture thallium ventricular functional information, while SPECT windows using optimized parameters can be applied to examine myocardial perfusion with thallium, and sites of myocardial apoptosis with Apomate.

ANTIBODY IMAGING

Beginning in 1994, the FDA approved a series of radiopharmaceutical agents that use proteins or protein fragments aimed at specific surface receptors abundant on targeted cells. The performance of In-111 OctreoScan is typical. The success of this agent, marketed by Mallinckrodt Medical, stems from its use of an octreotide, an analog of somatostatin. Octreotide binds to somatostatin receptors that are concentrated on the surfaces of various neuroendocrine cancer cells, making it a potent tool for detecting primary and metastatic neuroendocrine tumors.

In 1996, the FDA approved Immunomedics' CEA-Scan, a Tc-99m-labeled agent consisting of arcitumomab, a murine monoclonal antibody F(ab') fragment. It affixes itself to IMMU-4, a carcinoembryonic antigen (CEA) that is dispersed across the cell surface of gastrointestinal carcinomas.

The FDA subsequently approved Berlex's AcuTect and NeoTect. Tc-99m-labeled AcuTect detects acute venous thrombosis in the lower extremities. The key to its diagnostic power is a peptide targeted to the glycoprotein IIb/IIIa receptor on the surface of activated platelets, which are an indicator of acute clots. NeoTect employs a somatostatin targeting strategy to detect malignant lung tumors.

Tc-99m sestamibi (MIBI), a popular myocardial imaging agent, plays a second FDA-approved role in scintimammography and shows promise for measuring multidrug resistance to chemotherapy. In breast imaging, a decline in blood flow measured by MIBI uptake predicts the response of locally advanced breast cancer to neoadjuvant chemotherapy. High MIBI uptake after chemotherapy predicts poor survival, suggesting that imaging with the agent can serve as a surrogate end point during drug trials, said Dr. David A. Mankoff, an associate professor of radiology at the University of Washington.

MULTIDRUG RESISTANCE

SPECT lends insight to the Darwinian world of cellular multidrug resistance to therapy, said Dr. David Piwnica-Worms, director of molecular imaging at Washington University in St. Louis. Chemotherapy triggers natural selection, killing off susceptible cells while allowing resistant cells to replicate. Although cancer cells can employ various pathways to combat therapy, Piwnica-Worms has concentrated his research efforts on the so-called multidrug resistance gene and its product, P-glycoprotein. It is expressed in many tissue types, including the liver, where it pumps substrates into the bile, and the kidneys, where it pumps xenobiotics into the urine.

Some cancers overexpress P-glycoprotein to deal with toxins in the same way, Piwnica-Worms said. P-glycoprotein triggers a mechanism in a cancer cell's membrane that pumps chemotherapy out of the cell faster than it can be pumped in.

In research that began in the early 1990s, Piwnica-Worms and his colleagues found that radiopharmaceutical agents that have lipophilic or cationic properties can signal the presence or absence of P-glycoprotein. Tc-99m MIBI, Tc-99m tetrofosmin, Tc-99m Q58, and several C-11 PET agents share these characteristics, although MIBI has shown the most promise.

In the absence of P-glycoprotein, the lipophilicity of Tc-99m MIBI enables it to translocate across the cell membrane, and its cationic charge allows it to concentrate inside the cell and be sequestered in the mitochondria. Agent uptake is consequently high. With the presence of P-glycoprotein, Tc-99m MIBI acts like a therapeutic agent and is pumped out of the cell, so uptake is low. Because uptake is quantifiable, the radiopharmaceutical can measure the effectiveness of drugs designed to treat multidrug resistance, Piwnica-Worms said.

MEASURING ANGIOGENESIS

Quantitative measures of vascular permeability, glucose metabolism, blood flow, and blood volume relevant to tracking angiogenesis can be acquired with PET or SPECT, said Dr. King Li, director of intramural diagnostic imaging at the National Institutes of Health. Permeability may be measured with gallium-67 transferrin or radiolabeled albumin. Flow can be examined with Tc-99m MIBI or thallium 201. Blood volume measures can be obtained with Tc-99m red blood cell SPECT.

Tc-99m annexin V is used to target phosphatidylserine, a cell membrane phospholipid, to distinguish between necrosis and programmed cell death. In a recent clinical trial, Tc-99m annexin V was found to increase in patients who responded to chemotherapy but not in those whose disease progressed, Thrall said.

Tc-99m N-ethoxy-N-ethyl-dithiocarbamato-nitrido (NOET) is a neutral lipophilic agent with myocardial perfusion characteristics similar to those of sestamibi. A University of Maryland study suggests equivalence between NOET and MIBI in the heart, and a research team from Hotel-Dieu Hospital in Montreal presented data at the Society of Nuclear Medicine meeting in June implying a relationship between increased lung uptake of Tc-99m NOET and the subject's smoking history.

By measuring the dopamine transporter in the striatum of the basal ganglia, Tc-99m TRODAT-1 has gained acceptance for imaging Parkinson's disease.

At the 2002 SNM meeting, W.S. Huang and colleagues at the National Defense Medical Center in Taipei, Taiwan, compared imaging patterns acquired with Tc-99m TRODAT-1 SPECT and the clinical features of Parkinson's disease among a mix of 151 patients with idiopathic Parkinson's and healthy subjects to verify the utility of the dopamine transporter imaging technique. The procedure was 98% sensitive and 96% specific for diagnosing Parkinson's disease.

As a guidance tool, SPECT is gaining acceptance for imaging the biodistribution of Zevalin and other radioimmunotherapeutic agents before their administration. It is also used during stem cell implantation to determine whether the cells have been properly deployed, and afterward to measure their success in proliferating.