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CME

Novel Applications for PET: Emergent Agents, Alzheimer's Disease, and Addiction Imaging

  • Authors: Barry L. Shulkin, MD, MBA
  • THIS ACTIVITY HAS EXPIRED
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Target Audience and Goal Statement

This activity is intended for radiologists, nuclear medicine specialists, and oncologists, with an interest in integrating advanced imaging techniques such as PET scanning, PET/CT fusion, molecular imaging, and immunodiagnostics and immunotherapeutics into their practice to facilitate the early detection and clinical management of cancer.

The objective of this activity is to spotlight the clinical utility of advanced imaging studies such as PET scanning, PET/CT fusion, molecular imaging, and radioimmunotherapy in the detection, treatment, and monitoring of therapy for cancer; to define appropriate settings for the use of this technology; and to offer a venue for an expert in this aspect of imaging to outline the value of these technologies for the radiology, nuclear medicine, and oncology audiences on Medscape.

Upon completion of this activity, participants will be able to:

  1. Describe emergent novel tracer agents for PET scanning
  2. Discuss the ability of PET scanning to monitor response to treatment in cases of cancer
  3. Detail the utility of radiolabeled therapy for cancer
  4. Define expanding applications for PET, such as the assessment of Alzheimer's disease and addiction imaging


Author(s)

  • Barry L. Shulkin, MD, MBA

    Division of Nuclear Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, and St. Jude Children's Research Hospital, Memphis, Tennessee

    Disclosures

    Disclosure: Barry Shulkin, MD, MBA, has disclosed no relevant financial relationships.


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CME

Novel Applications for PET: Emergent Agents, Alzheimer's Disease, and Addiction Imaging

Authors: Barry L. Shulkin, MD, MBAFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

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New applications for positron emission tomographic (PET) scanning were showcased at a special session convened at the Annual Mid-Winter Meeting of the Society of Nuclear Medicine (SNM), February 11-12, 2006, Tempe, Arizona. A group of key opinion leaders outlined their work in areas such as addiction imaging and the evaluation of neurodegenerative disorders such as Alzheimer's disease.

Promising Agents for Oncology, as Discussed by Wolfgang Weber, MD, Associate Professor of Molecular and Medical Pharmacy, David Geffen School of Medicine, UCLA

Dr. Weber discussed 3 classes of "new" agents -- metabolic substrates, receptor ligands, and antitumor molecular probes. Fluorothymidine (FLT) is transported into cells via a pyrimidine transporter then phosphorylated. There have been 5 studies comparing FLT and fluorodeoxyglucose (FDG). These studies have examined colorectal carcinoma, melanoma, lymphoma, solitary pulmonary nodules/non-small-cell cancer, and breast cancer. The concentration of FLT in tumors (as measured by standardized uptake value [SUV]) is about half that of FDG. Dr. Weber showed a case of a colon cancer metastasis in the lung that had no uptake of FLT but intense uptake of FDG. FLT is not as good as FDG for staging. There is intense uptake in the liver and in the bone marrow. Buck and colleagues[1] examined the clinical relevance of FLT imaging in lung nodules. The authors studied 47 patients with newly diagnosed pulmonary nodules, 43 of whom also underwent FDG imaging. Thirty-two patients had malignancy, 9 of which were metastases from causes other than lung cancer. FLT imaging found 90% of lung cancers but only about 50% of mediastinal metastases. All benign lesions were negative. The authors concluded that FLT PET has high specificity for detection of malignant lung tumors but compared to FDG, FLT is less accurate for nodal staging and cannot be recommended for staging of lung cancer. In an earlier manuscript, they compared FLT and FDG imaging with proliferative activity. They found that FLT was a better index of proliferative activity than FDG.[2]

In a small study of patients with breast cancer, Smyyczek-Gargya and colleagues[3] found 13 of 14 malignant breast tumors were detectable with FLT in 12 patients. Seven of 8 patients with axillary metastases also had increased uptake. Although SUVs were lower than those with FDG, the contrast between tumors and background was high due to low uptake of FLT in surrounding breast tissue. In patients with colorectal carcinoma, all 6 primary tumors were depicted, yet only 11 of 32 liver metastases (34%) compared 33 of 34 on FDG imaging (97%).[4] In patients with esophageal cancer, FDG uptake was higher than FLT, FLT showed more false-negative findings (lower sensitivity) and fewer false-positive results (higher specificity).[5] In brain tumors, FLT uptake was rapid, peaking at only 5-10 minutes after injection.[6] Uptake in high-grade tumors was low but image contrast was higher than that of FDG, in part because of 5 false-negative FDG studies, and uptake of FLT in normal brain was quite low. FLT uptake correlated better with indices of tumor proliferation than did FDG and was a more power predictor of tumor progression and survival. Staging of tumors is thus limited by sensitivity, although specificity may be higher.

Dr. Weber next addressed the use of labeled choline. Choline in tissue is phosphorylated to phosphocholine, where it is trapped intracellularly to become part of membrane synthesis. Maximum uptake occurs within 5 minutes, thus transport is important. Choline derivatives have been synthesized that reflect transport only. In patients with prostate cancer, choline uptake has been assessed on a regional basis.[7] The sensitivity was 66% and specificity 81%. Kwee and colleagues[8] found evidence that fluorocholine (FCH) may also have potential for identifying prostate cancer . Price and colleagues[9] studied FCH in vitro and in vivo . They found higher uptake of FCH than FDG in the prostate bed, lymph nodes, and in bone deposits of prostate cancer. FCH cleared rapidly from the blood within about 2 minutes. Liver and renal activities were high. Schmid and colleagues[10] found a potential use for FCH in finding metastatic disease in patients whose PSA is rising, but they found no convincing evidence for its use in staging prostate carcinoma because the tracer uptake was also elevated in benign prostatic hypertrophy .

There are multiple somatostatin receptor binding compounds currently under investigation with the principal goal of developing a radiolabeled therapeutic agent. One recently described involves a carbohydrate conjugate to octreotide.[11] Called [18F]FP-Gluc-TOCA, this agent is cleared from the blood pool by the kidneys in the first hour and showed good uptake in liver lesions and abdominal foci of disease. The specific uptake in somatostatin receptor tissue (in the patient studied, a carcinoid) reached a plateau in the first hour. Other compounds, such as [68Ga]DOTA-Tyr3-octreotide and [64Cu]TETA-octretotide are also under investigation.[12,13]

PET of Alzheimer's Disease: An Update, as Discussed by Chester A. Mathis, PhD, Director of PET, Professor of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

This lecture focused on imaging of cerebrovascular amyloid.[14-17] Plaques, amyloid, and neurofibrillary tangles are found in patients with Alzheimer's disease but not in normal controls. An agent for imaging Alzheimer's disease must contribute something to the clinical examination, which is 50% to 90% sensitive and specific for Alzheimer's disease. In patients with Down's syndrome, amyloid deposits are present over 10 years before the onset of dementia. The hope is that by imaging amyloid before substantial damage to the brain is done, an intervention could be developed that could halt or reverse the progression of the disease. Neurofibrillary tangles in the mesial temporal lobe are found in 60-year-old normal patients who are cognitively sound and thought to be a part of normal aging. Amyloid imaging is being used to correlate the early cognitive decline with amyloid deposition and with the time course of deposition, test the amyloid cascade hypothesis -- that amyloid deposition in the cortex leads to neurofibrillary tangles and then to Alzheimer's disease. Amyloid imaging could aid in evaluation of therapeutic agents by monitoring the efficacy of treatment, establishing a homogenous patient population, and representing a surrogate end point for treatment.

Thioflavin T is a florescent dye that is selective for staining amyloid. Benzothiazole anilines (BTAs) are derivatives of thioflavin T. They do not bind to receptor sites in normal brain. One of these BTAs has been named Pittsburgh Compound B (PIB). It depicts amyloid fibrils in the brains of living transgenic mice. Binding assays from postmortem brains showed 10-fold greater binding to homogenates from patients with Alzheimer's disease (frontal and temporal cortex) compared to age-matched normal brain. No increase in binding was found in areas of patients with Alzheimer's disease that are not associated with amyloid fibrils, such as the cerebellum. Labeled with C-11, PIB has been administered in humans and measured using PET. There is increased retention of PIB in the brains of patients with Alzheimer's disease in areas known to contain large amounts of amyloid, and no increase in retention in unaffected areas. In both patients and controls, PIB retention was inversely correlated with FDG uptake.

The short-term role of amyloid imaging may be in the development of anti-amyloid therapies that focus on reducing the amyloid load in the brain.

Addiction Imaging, as Discussed by Joanna S. Fowler, PhD, Brookhaven National Laboratory, Brookhaven, New York

Addiction results from an interaction of an individual's environment, the drug of choice, and genetic biology. All drugs abused by humans raise dopamine levels in the nucleus accumbens, which is the reward center of the brain. Dopamine levels are elevated in feelings of well-being and in anticipation of rewards, such as highly palatable food.

Several tracers have been used to study addiction. These include FDG, C-11 cocaine, F-18F N-methylspiroperidol, C-11 raclopride, C-11 carfentanil, and others.[18-20]

Cocaine blocks the dopamine transporter on the presynaptic terminal. This leads to elevated dopamine concentration within synapses and stimulation of postsynaptic dopamine receptors. On average, cocaine addicts have lower numbers of D2 receptors than those in normal subjects, and D2 receptor numbers are lower in alcoholics, heroin abusers, and obese patients. This leads to the conclusion that, in addiction, a reward circuit is stimulated by the drug.

A target for nicotine is monoamine oxidase (MAO), an enzyme that metabolizes neurotransmitter amines. It occurs in 2 forms that have different specificities. PET studies of cigarette smokers have found a 30% and 40% reduction in MAO-A and MAO-B, respectively. With tobacco cessation, MAO levels return to normal. Smokers have a decreased incidence of Parkinson's disease, and this raises the question whether tobacco smoke may be neuroprotective for this disease. Reduced intracellular MAO in smokers may leave more dopamine available for neurotransmission. Most addicts smoke -- 90% of alcoholics, 85% of schizophrenics, 80% of depressed patients, compared with about 25% in the general population. Are smokers self-regulating dopamine levels?

Inhalant abuse is rapidly growing, and toluene is the most abused inhalant. Toluene elevates the level of dopamine in the prefrontal cortex and precipitates extensive white matter damage in the brain.

The study of addictive behaviors has been abetted by advances in chemistry allowing rapid synthesis of tracers, analysis of their kinetics that leads to new knowledge, and new treatment approaches. Dr. Fowler stressed the need for more chemists. Understanding addiction and development of new treatments or modification would impact many areas of healthcare and have far-reaching consequences in heart disease (due to smoking), cancer (due to tobacco), AIDS, auto accidents due to alcohol, obesity, and violence (for example, violence caused by an individual who is a drug addict).

References

  1. Buck AK, Hetzel M, Schirrmeister H, et al. Clinical relevance of imaging proliferative activity in lung nodules. Eur J Nucl Med Mol Imaging. 2005;32:525-533. Abstract
  2. Buck AK, Halter F, Schirrmeister H, et al. Imaging proliferation in lung tumors with PET: 18-FLT versus 18F-FDG. J Nucl Med. 2003 ;44:1426-1431. Abstract
  3. Smyczek-Gargya B, Rersis N, Dittman H, et al. PET with [18F] fluorothymidine for imaging of primary breast cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2004;19:436-442.
  4. Francis DL, Visvikis D, Costa DC, et al. Potential impact of [18F]3'-fluorothymidine versus [18F]fluoro-2-deoxy-D-glucose in positron emission tomography for colorectal cancer. Eur J Nucl Med Mol Imaging. 2003;30:988-994. Abstract
  5. Van Westreenen HL, Cobben DC, Jager PL, et al. Comparison of 18F-FLT PET and 18F-FDG PET in esophageal cancer. J Nucl Med. 2005;46:400-404. Abstract
  6. Chen W, Cloughesy T, Kamdar N, et al. Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med. 2005;46:945-952. Abstract
  7. Farsad M, Schiavina R, Castellucci P, et al. Detection and localization of prostate cancer: correlation of (11)C-choline PET/CT with histopathologic step-section analysis. J Nucl Med. 2005;46:1642-1649. Abstract
  8. Kwee SA, Coel MN, Lim J, Ko JP. Prostate cancer localization with 18fluorine fluorocholine positron emission tomography. J Urol. 2005;173:252-255. Abstract
  9. Price DT, Coleman RE, Liao RP, Robertson CN, Polascik TJ, DeGrado TR. Comparison of [18 F]fluorocholine and [18 F]fluorodeoxyglucose for positron emission tomography of androgen dependent and androgen independent prostate cancer. J Urol. 2002;168:273-280. Abstract
  10. Schmid DT, Zweifel JH, Cservenyak T, et al. Fluorocholine PET/CT in patients with prostate cancer: initial experience. Radiology. 2005;35:623-628.
  11. Wester HJ, Schottelius M, Schedihauer K, et al. PET imaging of somatostatin receptors: design, synthesis and preclinical evaluation of a novel 18F-labelled, carbohydrated analogue of octreotide. Eur J Nucl Med Mol Imaging. 2003;30:117-122. Abstract
  12. Beer AJ, Haubner R, Goebel M, et al. Biodistribution and pharmacokinetics of the alphavbeta3-selective tracer 18F-galacto-RGD in cancer patients. J Nucl Med. 2005;46:1333-1341. Abstract
  13. Wu Y, Zhang X, Xiong Z, Cheng Z, Fisher DR, Liu S, Gambhir SS, Chen X. microPET imaging of glioma integrin alpha v beta3 expression using (64)Cu-labeled tetrameric RGD peptide. J Nucl Med. 2005;46:1707-1718. Abstract
  14. Lopresti BJ, Klunk WE, Mathis CA, et al. Simplified quantification of Pittsburgh compound B amyloid imaging PET studies: a comparative analysis. J Nucl Med. 2005;46: 1959-1972. Abstract
  15. Mathis CA, Klunk WE, Price JC, DeKosky ST. Imaging technology for neurodegenerative diseases: progress toward detection of specific pathologies. Arch Neurol. 2005;62:196-200. Abstract
  16. Wang Y, Klunk WE, Debnath ML, et al. Development of a PET/SPECT agent for amyloid imaging in Alzheimer's disease. J Mol Neurosci. 2004;24:55-62. Abstract
  17. Mathis CA, Wang Y, Klunk WE. Imaging beta-amyloid plaques and neurofibrillary tangles in the aging human brain. Curr Pharm Design. 2004;10:1469-1492.
  18. Benveniste H, Fowler JS, Rooney W, et al. Maternal and fetal 11C-cocaine uptake and kinetics measured in vivo by combined PET and MRI in pregnant nonhuman primates. J Nucl Med. 2005;46:312-320. Abstract
  19. Volkow ND, Fowler JS, Wolf AP, et al. Distribution and kinetics of carbon-11-cocaine in the human body measured with PET. J Nucl Med. 1992;33:521-525. Abstract
  20. Volkow ND, Fowler JS, Wang G-W. Positron emission tomography and single photon emission computed tomography in substance abuse research. Semin Nucl Med. 2004;33:114-128.