An Introduction to Newer PET Diagnostic Agents and Related Therapeutic Radiopharmaceuticals
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An Introduction to Newer PET Diagnostic Agents and Related Therapeutic Radiopharmaceuticals Ellie Mantel, CNMT, RT(N), FSNMMITS1 and Jessica Williams, CNMT, RT(N), FSNMMITS2 1Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania; and 2Molecular Imaging Department, Harley Street Clinic, HCA Healthcare, London, England CE credit: For CE credit, you can access the test for this article, as well as additional JNMT CE tests, online at https://www.snmmilearningcenter.org. Complete the test online no later than September 2022. Your online test will be scored immediately. You may make 3 attempts to pass the test and must answer 80% of the questions correctly to receive 1.0 CEH (Continuing Education Hour) credit. SNMMI members will have their CEH credit added to their VOICE transcript automatically; nonmembers will be able to print out a CE certificate upon successfully completing the test. The online test is free to SNMMI members; nonmembers must pay $15.00 by credit card when logging onto the website to take the test. imaging protocols have yet to be finalized. The objective of With new radiopharmaceuticals constantly in development, the this paper is to provide an overview of newer radiopharma- field of nuclear medicine is ever evolving. This continuing ceuticals and their uses related to neuroendocrine tumors education article reviews some of the newer, less frequently (NETs), prostate cancer, Alzheimer disease, and coronary artery used radiopharmaceuticals for PET diagnostic imaging and disease. related therapeutic protocols. The radiopharmaceuticals dis- cussed include U.S. Food and Drug Administration–approved RADIOPHARMACEUTICALS FOR NETS tracers as well as tracers that are in clinical trials and have yet to obtain Food and Drug Administration approval. This article con- The neuroendocrine system comprises specialized nerve tains straightforward information on each tracer discussed, in- cells that receive messages from the nervous system and cluding disease process imaged or treated, half-life, energy, then produce hormones (1). These hormones control many primary uses, basic protocols, distribution, and side effects. body functions. NETs are relatively rare tumors, with fewer Although not all tracers may be available in rural locations, this information can be helpful in determining future patient-care than 200,000 reported cases in the United States annually. They offerings. do not consume glucose and generally manifest as an over- Key Words: neuroendocrine tumor; prostate cancer; Alzheimer expression of the hormone somatostatin or norepinephrine (2). disease; amyloid imaging; cardiovascular imaging; neurologic Not all NETs are malignant; some are benign, but the PET imaging malignant tumors can metastasize. NETs are slow-growing J Nucl Med Technol 2019; 47:203–209 tumors occurring in a variety of locations within the neuro- DOI: 10.2967/jnmt.118.224022 endocrine system. For example, carcinoid tumors, which can form in many areas of the body, most commonly are found in the digestive system, including the stomach, small intestine, appendix, and rectum. NETs can also develop in the lungs and thymus, and although it is less likely, they can As nuclear medicine and molecular imaging continue to develop in the pancreas, ovaries, testicles, and kidneys. grow and expand, so does the number of radiopharmaceu- Because NETs can occur in such varied locations, they are ticals that are available in our imaging and therapeutic not typically diagnosed until they reach advanced stages. arsenal. Numerous new radiopharmaceutical tracers have There are multiple types of NETs, including pheochro- been developed for diagnostic PET and therapeutic appli- mocytoma, medullary carcinoma, gastrinoma, insulinoma, cations. Not all radiopharmaceuticals discussed in this ar- pancreatic NET, and paraganglioma, to name a few. Depend- ticle are Food and Drug Administration (FDA)–approved; ing on the type of tumor, some NETs also secrete hormones, however, most are approved but may be geographically with symptoms varying depending on the type of NET. limited in availability. For radiopharmaceuticals still in Several somatostatin analog tracers have been labeled the clinical trial phase, specific patient preparation and with 68Ga and used for imaging, including DOTATATE, DOTATOC, and DOTANATE. DOTATATE has been in use Received May 21, 2018; revision accepted Feb. 20, 2019. in Europe for over 10 y; however, it only recently received For correspondence or reprints contact: Ellie Mantel, CNMT, RT(N), FSNMMI-TS, Hospital of the University of Pennsylvania, 745 Valley Ave., approval in the United States from the FDA in 2016. Hammonton, NJ 08037. DOTATATE, DOTATOC, and DOTANATE are somato- E-mail: [email protected] Published online Apr. 24, 2019. statin receptor peptides primarily used to determine whether COPYRIGHT © 2019 by the Society of Nuclear Medicine and Molecular Imaging. a patient’s tumor is somatostatin receptor–positive. Determining NEW PET RADIOPHARMACEUTICALS • Mantel and Williams 203 somatostatin receptor status is essential for treatment plan- ning because not all NETs are somatostatin receptor–posi- tive. Patients with somatostatin receptor–positive NETs are ideal candidates for 177Lu or 90Y-DOTA somatostatin ana- log therapies. In addition to determining the receptor status of the tumor, somatostatin analog imaging aids physicians in identifying the presence and extent of metastatic disease throughout the body. Diagnostic doses are also used to monitor a patient’s response to therapy or disease progression (3). 68Ga-DOTATATE Imaging 68Ga-DOTATATE (NETSPOT; Advanced Accelerator Ap- plications) is a radioactive diagnostic agent that is approved for the localization of somatostatin receptor–positive NETs. 68Ga is generator-produced from 68Ge, which has a half-life of 270 d (4). This long half-life allows a nuclear pharmacy to use the generator for 6–12 mo depending on the number of elutions. The expiratory limit is approximately 550 elutions (recently increased from the previously reported 400 total elutions). Total elutions include patient doses as well as the weekly quality control elution. Quality control on the generator eluate is performed weekly to determine germa- FIGURE 1. Two images from same patient obtained 3 wk nium breakthrough. Additionally, quality control of the gen- apart: planar 111In-octreotide scan (A) and 68Ga-DOTATATE erator eluate must also be performed if the generator has PET scan (B). Lesions within liver are more easily identified on been moved or if more than 72 h have elapsed between higher resolution of PET scan than on planar octreotide scan. elutions. The generator can be eluted up to 3 times each day at intervals of 4 h to allow for a 90% maximum yield. nuclear imaging departments do not have PET equipment, 68Ga has a half-life of 68 min and decays by positron and second, access to 68Ga-DOTATATE is geographically con- emission to stable 68Zn. Because of its short half-life, coordi- strained to areas close to a nuclear pharmacy. nation between the imaging site and the nuclear pharmacy preparing the 68Ga-DOTATATE kit is essential. Additionally, 177Lu-DOTATATE Therapy a rural institution’s geographic location may be a limiting 177Lu-DOTATATE (Lutathera; Advanced Accelerator Appli- factor in performing 68Ga-DOTATATE imaging. cations) is a reactor-produced therapeutic radiopharmaceutical The recommended adult and pediatric dose is weight- for the treatment of NETs (6). 177Lu has ideal physical properties based at 2 MBq/kg (0.054 mCi/kg), with a maximum dose for use in cancer treatment, including a particle range of 1.5 mm, of 200 MBq (5.4 mCi) administered via intravenous a half-life of 6.73 d, and being a b-emitter (490 keV) and injection (4,5). No specific patient preparation is required g-emitter (113 keV and 210 keV), allowing for both treatment with the exception of discontinuing short-acting somatostatin and imaging (7). Although this radiopharmaceutical has analogs (e.g., octreotide) 24 h before 68Ga-DOTATATE ad- been used in Europe for more than 10 y, it only recently received ministration. Imaging is performed 40–90 min after admin- FDA approval in January 2018. Peptide receptor radionuclide istration of 68Ga-DOTATATE. For PET/CT imaging, oral therapy is a cancer treatment that uses the characteristics of a barium contrast medium may be administered at the time cancer cell to deliver the radiation. A group of amino acids called of injection. Images are acquired from skull to mid thigh peptides is sometimes found on the surface of the cell, and these with the patient supine. peptides have the ability to bind to certain hormones. In Normal distribution of 68Ga-DOTATATE includes liver, peptide receptor radionuclide therapy, the receptor on the kidneys, bladder, bowel, spleen, pituitary, salivary glands, surface of the cancer cell binds to a peptide, which is paired thyroid, and adrenal medulla (Fig. 1). The spleen and the with a radionuclide. This combination of peptide and radionuclide urinary bladder wall receive the highest absorbed dose. is called a radiopeptide. The radiopeptide is then admin- Approximately 12% of the injected dose will be excreted istered intravenously and seeks cancer cells’ somatostatin re- in the urine within 4 h of dose administration. ceptors. After attaching to the cancer cells, the radiopeptide As would typically be expected, the resolution of the delivers radiation directly to the cells (8). 68Ga-DOTATATE PET scan is better than that