Fifty Years of Radiopharmaceuticals

THE 1970S

As far back as the 1970s, the field of radiopharmaceuticals has involved both innovations in chemistry and adaptation to regulatory reform. In 1970, the U.S. Food and Drug Administration (FDA) announced its plans to withdraw exemptions granted to radiopharmaceuticals and begin regulating them as drugs. This process was completed in 1977, after which time new-drug applications were required to market new and existing radiopharmaceuticals. From a chemistry perspective, this decade included key developments in the use of ²⁰¹Tl for myocardial perfusion imaging (10), as well as ⁸⁹Sr to reduce the pain associated with metastatic bone disease (11). Interestingly, early attempts to use labeled antibodies for tumor imaging were also pioneered by Primus et al. (12). However, the 1970s are likely remembered best for milestones in ^99mTc chemistry and ¹⁸F-FDG. After the introduction of the ^99mTc generator in the 1950s (13), and the realization by Richards that ^99mTc has medical utility (14), the 1970s saw significant efforts to develop new ^99mTc-based radiopharmaceuticals. For example, Loberg and Fields discovered the substituted iminodiacetic acid analogs for hepatobiliary imaging (15). The development of these compounds, radiolabeled with ^99mTc, was an early example of the concept of bifunctional chelators, that is, ligands that are designed to both chelate and target biodistribution of the ^99mTc complex. The 1970s also saw the introduction of the ^99mTc-diethylenetriaminepentaacetic acid instant kit for renal imaging by Eckelman and Richards (16).

Ido and colleagues, at Brookhaven National Laboratory, were the first to describe the synthesis of ¹⁸F-FDG (17). The first clinical PET scan with ¹⁸F-FDG, in 1976, was likely the most important milestone of this decade. ¹⁸F-FDG remains the mainstay of clinical PET imaging to this day and makes up most clinical PET scans that are performed in the United States each year. The ¹⁸F-FDG was manufactured at Brookhaven National Laboratory in August 1976 and then flown to Philadelphia, where it was first administered by Alavi at the University of Pennsylvania to 2 healthy human volunteers (18). At the time, the interest was in neuroscience applications, and images obtained with an ordinary nuclear scanner showed uptake of ¹⁸F-FDG in the brain.

THE 1980S

^99mTc chemistry grew further during the 1980s, and in 1985, Ell reported the first instance of cerebral blood flow imaging using ^99mTc-exametazime, developed by Amersham (19). By 1988, the FDA had approved this for diagnosis of stroke. At the University of Michigan in the early 1980s, Kline et al. developed meta-iodobenzylguanidine for imaging and treatment of neuroblastoma and other adrenergic tumors in the body, as well as myocardial imaging (20,21). In oncology, ¹²³I-meta-iodobenzylguanidine was used to stage disease, and it was found that ¹³¹I-meta-iodobenzylguanidine could be used for both imaging and therapy. By the late 1980s, ¹³¹I-meta-iodobenzylguanidine was being used for the detection and treatment of malignant pheochromocytomas and neuroblastomas, as well as myocardial imaging.

The 1980s were also an active decade for PET research. For example, 1989 saw the FDA approval of ⁸²Rb for PET myocardial perfusion imaging (22), and the discovery that ¹⁸F-FDG accumulates in tumors began the evolution of PET as a major clinical tool in cancer diagnosis that continues to this day (23). Brodack et al. were also developing ¹⁸F-labeled ligands for estrogen receptors (24), while Jerabek and colleagues reported ¹⁸F-fluoromisonidazole for tumor hypoxia imaging (25). The 1980s in many ways also represented the golden age of PET in neuroscience. Henry Wagner reported the first imaging of neuroreceptors in humans. Using himself as the subject, Wagner, along with his coworkers, imaged dopamine receptors using 3-N-¹¹C-methylspiperone (26). At about the same time, Crawley et al. was using ⁷⁷Br-p-bromospiperone to image dopamine receptors in the U.K. (27). Concurrent with efforts to image dopamine receptors, Garnett et al., who were working at McMaster University in Canada, described the first distribution of dopamine in the basal ganglia using ¹⁸F-6-fluoro-DOPA (28). As a side note, Eckelman and Reba also carried out the first example of SPECT neuroreceptor imaging using ¹²³I-3-quinuclidinyl-4-iodobenzilate to image muscarinic acetylcholine receptors in Alzheimer disease (29). All of this work established the use of functional imaging in neuroscience applications and stimulated development of many new radiopharmaceuticals for brain imaging. For example, the 1980s would see Fowler et al. introduce ¹¹C-deprenyl for imaging of monoamine oxidase (30), Herscovitch et al. measure cerebral blood flow with ¹⁵O-water and ¹¹C-butanol (31), and Dannals et al. at Johns Hopkins image μ-opioid receptors with ¹¹C-carfentanil (32). It is interesting to look back and recognize that the desire to develop new radiopharmaceuticals in this period was also driving innovation in synthesis and radiochemistry and that even in the 1980s, radiochemists were thinking about new precursors for radiochemistry (33), automation (34) and strategies for simplified purification of radiopharmaceuticals (35).

THE 1990S

The 1990s saw FDA approval of ^99mTc-sestamibi as the first ^99mTc myocardial agent. ^99mTc-Sestamibi is still widely used today, mainly for myocardial imaging but also to identify parathyroid adenomas, for radioguided surgery of the parathyroid, and in breast cancer imaging (36). Other developments in SPECT imaging included the first FDA-approved monoclonal antibody for tumor imaging, ¹¹¹In-satumomab pendetide (37).

This decade was also a turning point for PET imaging, as approval of ¹⁸F-FDG by the U.S. FDA was seen, as well as subsequent reimbursement by the Centers for Medicare and Medicaid Services. Automated-synthesis modules were introduced for its production, and pharmacy networks were established for commercial distribution to satellite PET centers without a cyclotron. Use of ¹⁸F-FDG grew substantially, and new applications emerged, such as the prediction and assessment of tumor response to therapy. Since that time, the use of ¹⁸F-FDG PET for imaging applications in oncology, neurology, and cardiology has grown steadily, and reflecting this growth, the estimated number of ¹⁸F-FDG PET studies that occurred in the United States in 2017 was more than 1.9 million.

THE 2000S

The 2000s saw a number of substantive changes in the field, from the development of hybrid PET/CT scanners in 2000 (the Siemens Biograph was Time Magazine’s Invention of the Year in 2000) (38) to the introduction of good-manufacturing-practice regulations for radiopharmaceuticals (title 21 of Code of Federal Regulations, part 212) by the U.S. FDA in 2009 (39). The 2000s were also an important time for PET imaging. The pioneering work of Klunk et al. in developing ¹¹C-Pittsburgh compound B for imaging amyloid plaques in dementia patients came to fruition, and they reported the first human studies in 2004 (40). This work sparked the widespread use of PET imaging as a tool in dementia research and led to the more recent establishment of multiple-site clinical studies (e.g., the Alzheimer’s Disease Neuroimaging Initiative (41)) and the use of PET to support therapeutic trials (42). Besides use in clinical trials, the use of PET as a serious tool to support drug discovery efforts began with, for example, work from Bergström et al. at Merck using PET to inform go/no-go decisions on therapeutic assets such as aprepitant (Emend; Merck) (43).

The emerging role for radiotherapeutics in general clinical care also began during the 2000s. The FDA approved Zevalin (ibritumomab tiuxetan [Acrotech Biopharma], a monoclonal antibody radioimmunotherapy treatment for relapsed or refractory, low-grade or transformed B-cell non-Hodgkin's lymphoma) and Bexxar (unlabeled tositumomab combined with ¹³¹I-labeled tositumomab, approved for treatment of relapsed or chemotherapy/rituxan-refractory non-Hodgkin lymphoma [GlaxoSmithKline]).

THE 2010S

The 2010s were an extremely exciting time for the radiopharmaceutical sciences and nuclear medicine, as both disciplines matured from research techniques to underpin powerful standards of care. For example, ¹²³I-DaTscan (¹²³I-ioflupane [GE Healthcare]), under development since the 1990s, was approved by the FDA in 2011 to help differentiate essential tremor from tremor due to Parkinsonian syndromes (44).

Title 21 of Code of Federal Regulations, part 212, mandated that anyone marketing PET drugs in the United States was required to obtain FDA approval by filing new-drug applications or abbreviated new-drug applications (39). This change moved PET radiopharmaceutical production from the practice of pharmacy to FDA-regulated drug manufacture and saw commercial nuclear pharmacies and academic medical centers alike obtain FDA approval for established radiopharmaceuticals such as ¹⁸F-FDG (oncology, neurology, and cardiology), ¹⁸F-NaF (bone imaging), and ¹³N-ammonia (myocardial perfusion imaging). In many ways, title 21 of Code of Federal Regulations, part 212, clarified the path forward for obtaining regulatory approval and marketing authorization for new PET drugs as well. Reflecting this clarity, the 2000s witnessed FDA approval of numerous new PET radiopharmaceuticals for imaging. For example, in the neuroimaging space, Amyvid (florbetapir, 2012 [Eli Lilly]), Vizamyl (flutemetamol, 2013 [GE Healthcare]), and Neuraceq (florbetaben, 2014 [Life Molecular Imaging]) were all approved for PET imaging of the brain to estimate β-amyloid neuritic plaque density in adult patients with cognitive impairment who are being evaluated for Alzheimer disease and other causes of cognitive decline.

In oncology, the Mayo Clinic obtained FDA approval for ¹¹C-choline, and Blue Earth Diagnostics received approval for Axumin (¹⁸F-fluciclovine), both to image patients with suspected prostate cancer recurrence. This decade also saw a paradigm shift in radiotherapy and theranostics. In 2013, Bayer obtained FDA approval of Xofigo (²²³RaCl₂) for the treatment of patients with castration-resistant prostate cancer (and symptomatic bone metastases) and, perhaps for the first time, demonstrated that a big pharmaceutical company could successfully market a radiotherapeutic. Later in the decade, FDA approval of Netspot (⁶⁸Ga-DOTATATE) and Lutathera (¹⁷⁷Lu-DOTATATE) was obtained by Advanced Accelerator Applications (which was subsequently purchased by Novartis), and FDA approval for ⁶⁸Ga-DOTATOC was granted to the University of Iowa (45). Netspot and DOTATOC are indicated for localization of somatostatin receptor–positive neuroendocrine tumors with PET imaging, whereas Lutathera is a radiolabeled somatostatin analog indicated for the treatment of somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors. These agents have ushered nuclear medicine into a new era of theranostics (46), and analogous agents targeting the prostate-specific membrane antigen and labeled with diagnostic (¹⁸F, ⁶⁸Ga) or therapeutic (²²⁵Ac, ¹⁷⁷Lu) radionuclides are currently in advanced clinical trials all over the world for diagnosis and treatment of prostate cancer.

2020 AND BEYOND

The growth in the radiopharmaceutical sciences and nuclear medicine in the last 50 years has been impressive. However, as we turn our gaze to the future, it is possible that the best is yet to come. New diagnostic and therapeutic radiopharmaceuticals are being approved by the FDA, heralding in the age of theranostics, and we expect this trend to continue. Advances in the production and availability of new isotopes such as ⁸⁹Zr, ^52gMn, ⁸⁶Y, ^43,47Sc, ⁵⁵Co, and many others are expanding the chemistry toolbox for the synthesis of new radiopharmaceuticals. At the same time, advances in technology (e.g. mini cyclotrons, new synthesis module paradigms, and miniaturized equipment for automated quality control testing) are facilitating wider access to radiopharmaceuticals, particularly in developing nations. These developments, in conjunction with potentially disruptive new technologies such as total-body PET (47), could change the radiopharmaceutical paradigm. In addition to the impact on clinical scanning, total-body PET may have implications for the traditional commercial distribution model for radiopharmaceuticals. For example, the increased sensitivity of these new scanners allows the use of smaller amounts of injected activity. This change could permit a longer-range distribution of established radionuclides such as ¹⁸F while also potentially enabling routine distribution of shorter-lived radionuclides such as ¹¹C and ⁶⁸Ga for the first time. All these developments make this an extremely exciting and rewarding time to be in the field of radiopharmaceutical sciences, and we at the Radiopharmaceutical Sciences Council are passionate about our mission to provide a forum for discussion and dissemination of information on the radiopharmaceutical sciences, to promote and encourage basic research and applied technology in the radiopharmaceutical sciences, and to provide the SNMMI with information on the radiopharmaceutical sciences. We are also actively engaged in supporting and training the next generation of radiopharmaceutical scientists and committed to working with the SNMMI and SNMMI-TS to ensure a bright future for our field. We congratulate the SNMMI Technologist Section on its 50th anniversary, and we look forward to the new developments that occur in the next 50 years.

DISCLOSURE

No potential conflict of interest relevant to this article was reported.