One Hundred Years of the Tracer Principle

This year, the tracer principle, a key concept within nuclear medicine, molecular imaging, and radiotheranostics, is marking the centennial anniversary of its discovery (Fig. 1). Although Marie Curie pioneered the concept of using external radiation to diagnose and treat cancer during World War I, the first use of radioactivity to quantify a biologic process was reported by George de Hevesy in May 1923 (1). De Hevesy, a Nobel Prize winner, measured the uptake of radioactive lead (²¹⁰Pb; at that time, thorium-B) in plants, in most cases fava beans, by electroscopic analyses (2) of their ashes. This experiment showed dose-dependent lead uptake in plants and revealed that radioactive lead can be displaced by stable lead and vice versa. But these findings followed an initial failure in 1911, when de Hevesy unsuccessfully tried to separate radioactive lead from stable lead (3). The initial experiment was performed at the request of Nobel Prize winner Ernest Rutherford (4), who developed an atomic model in 1911 that was later expanded on by Niels Bohr. Nevertheless, de Hevesy’s initial failure at the impossible separation ultimately led to the birth of the tracer method. He recognized that since both substances (in today’s terminology, the stable and the radioactive isotopes) are inseparable, they must be chemically and biologically identical. And hence, the measurable radioactive isotope can be used as an indicator for the corresponding stable isotope to quantify biologic processes.

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FIGURE 1.

Representative milestones of hundred-year journey of tracer principle from 1923 to 2023. FDA = Food and Drug Administration; SSTR = somatostatin receptor.

After de Hevesy’s 1923 report, the use of radioactive isotopes to quantify biologic processes rapidly escalated, with applications in plants, animals, and humans. In 1927, Blumgart and Weiss published the use of ²¹⁴Bi to measure the blood circulation time from one arm to the other in both healthy individuals and patients and thus were the first to apply a radioactive substance for diagnostic purposes in humans (5–7). This effort is commonly considered the birth of clinical nuclear medicine (5) and led to enormous interest in using radioactive isotopes for medical applications. In the following period—until the mid 1930s—a major drawback to this approach became apparent, as the availability of radioactive isotopes of elements with biologic function was limited to those that were naturally occurring (e.g., phosphorus [³²P] or potassium [⁴⁰K]), which were generally not obtainable in quantities useable for diagnostic purposes.

The invention of the cyclotron by Ernest Lawrence in the early 1930s at the University of California Berkeley (8,9) and, shortly after, the discovery of artificial radioactivity by Joliot and Curie (10) and Enrico Fermi (11) opened the possibility for the early success of what later became nuclear medicine. ^99mTc, the diagnostic workhorse of the radioisotopes, was first synthesized in 1938 in Berkeley, California, as well (12). Although it was not the first therapeutically used radionuclide (13), the early availability of several radioactive iodine isotopes (i.e., ¹²⁸I, ¹³⁰I, and ¹³¹I) enabled the first radioiodine therapy by Saul Hertz in 1941 (14), which paved the way for broad application of radioactive tracers in humans. Of particular interest, the use of radioiodine-based diagnostic imaging combined with radioiodine-based therapy was a profoundly important demonstration of the use of theranostics, long before that term became en vogue (15). Within the next few years, the implementation of nuclear medicine in clinical practice took place worldwide. Eighty years later, radioiodine therapy remains a cornerstone for the treatment of thyroid diseases (16).

After World War II, isotopes for both diagnostic and therapeutic applications could be synthesized on a large scale, and within the next few years the bottleneck was widened. Development of radioactive tracers for new target structures became of significant importance, particularly since the thyroid–iodine relationship was unique. Along with radiochemistry, development of new instrumentation with improved detection and visualization of radioactivity within the human body became the driver of innovation in early nuclear medicine.

By the 1950s, important advancements were made in instrumentation development, starting with electrography and Geiger–Müller tubes via the first rectilinear scanners and planar γ-cameras and subsequently improved on by the implementation of photomultipliers by Anger (17). The first steps toward positron emission imaging were made in the early 1950s by Sweet and Brownell at the Massachusetts General Hospital (18). In the same decade, Ter-Pogossian et al. studied respiratory and cerebral metabolism and oxygen tension in malignant tumors using the positron emitter ¹⁵O (19). The first modern transaxial PET scanner, which lead to the modern devices that we know today, was developed in the mid-1970s by the group of Phelps, Hoffman, and Ter-Pogossian at Washington University (19,20). In 1975, the group of Sokoloff at the National Institutes of Health reported for the first time the use of the tracer principle to investigate glucose metabolism (21). [¹⁴C]deoxyglucose was used in ex vivo experiments to assess cerebral glucose consumption using autoradiographic measures of the central nervous system. The first PET images depicting glucose metabolism in the human body using ¹⁸F-FDG were acquired at the University of Pennsylvania in the following year (22).

¹⁸F would prove to be the ideal radionuclide for PET imaging given its combination of a 108-min half-life, high positron yield, low positron energy, cyclotron production, and isosterism with hydrogen. After almost half a century, ¹⁸F-FDG remains the most versatile radioactive tracer in nuclear medicine, with impact across multiple disciplines, such as oncology, neurology, cardiology, and infectious diseases. The progress in the development of imaging devices and tracer design was accompanied by an important milestone in image processing, when Dahlbom et al. pioneered at UCLA the first whole-body PET reconstruction method (23).

In the late 1970s, receptor-binding tracers started to be discussed as a promising new class of radiopharmaceuticals (24). The first receptor-binding tracer was administered in humans by Henry Wagner in 1983 at the Johns Hopkins University; that is, 3-N-[¹¹C]methylspiperone was applied to image neurodopamine receptors (25). But receptor-based systems were more complex than previously used active transport radiopharmaceuticals (e.g., iodide taken up by the thyroid). Parameters such as target-to-nontarget ratio, receptor affinity, and saturation ought to be considered for the interaction between receptor and radiopharmaceutical; in addition, the administered radioactivity needed to be optimized on the basis of this interaction. But the new class of receptor-binding tracers has proven to be instrumental for the future development of nuclear medicine. Particularly, the discovery of small-molecule prostate-specific membrane antigen (PSMA) ligands in the early 2000s has been transformative for nuclear medicine in the modern era of molecular imaging and radiotheranostics (26–28). Two decades later, small-molecule PSMA ligands were approved by the U.S. Food and Drug Administration for diagnosis and treatment of prostate cancer (29–31). Notably, the initial U.S. Food and Drug Administration approval of ⁶⁸Ga-PSMA-11 PET was accomplished as a joint academic effort at UCLA and the University of California, San Francisco (30,32,33). But clinical translation of PSMA ligands followed 2 other major successes in nuclear medicine, that is, approval of the α-emitter ²²³Ra for advanced, bone-metastatic prostate cancer (34) and the somatostatin receptor-targeted radiotheranostics for neuroendocrine tumors (35). Overall, these recent successes have shifted the focus of radiopharmaceutical drug discovery toward development of receptor-binding radiopharmaceuticals that can be used as a pair for imaging (diagnostic biomarker) and therapeutic purposes in malignancies, so-called radiotheranostics (36). Several promising radiotheranostic agents are currently in different phases of clinical development and may soon expand the role of nuclear medicine in oncology. These include radiopharmaceuticals targeting the fibroblast activation protein tested in several solid malignancies including pancreatic cancer and sarcoma (37); the C-X-C chemokine receptor 4 in hematologic malignancies (38); the gastrin-releasing peptide receptors in prostate cancer, breast cancer, or small cell lung cancer (39); or the human epidermal growth factor receptor 2 in breast cancer (40,41). The continuous expansion of the radiopharmaceutical portfolio together with the recent development of PET instrumentation, that is, total-body digital PET scanners (42), may enable quantification of biologic process by molecular imaging at an unprecedented detail level.

With this short historic overview, we would like to pay tribute not only to de Hevesy and the fava beans but also to the humorous historical essay of Marshall Brucer from 1978 (43). Brucer tracked down the history of nuclear medicine to its roots in 1815, when William Prout detected uric acid and determined the atomic weight of urea in the feces of the boa constrictor. When researching for the next big thing in nuclear medicine after radioiodine, ¹⁸F-FDG, or PSMA ligands, one may account for de Hevesy’s initial failure and frustration, which ultimately led to the successful use of radioactive lead in the ashes of fava beans. We should see more in fava beans than a side dish for liver and Chianti or the mascot of a midsized German town called Erfurt (44). We are even still facing some of the same challenges that our early forebears faced: a century after medical use of radioactive tracers was curtailed by the availability of only naturally occurring isotopes, the nuclear medicine community is facing a similar issue, that is, a shortage of [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto; Novartis) due to the “unexpected” high demand of the radiopharmaceutical after approval (45).

This hundred-year journey of the tracer principle is promising a bright future for the field of nuclear medicine, molecular imaging, and radiotheranostics, which may have reached its prime time to become an independent specialty in the United States (46).

• © 2023 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication July 26, 2023.
• Revision received September 27, 2023.