In contemplating peer-reviewed information and the business of science divulgation, in which we all are immersed, one may wonder what legacy a very quoted article will hand down to posterity and what core of knowledge will stand the tests of time, of fashion, and of planned obsolescence of intellectual production (1).
Somatostatin receptor theranostics, as we know them today, need to be inscribed in the history of neuroendocrine tumors (NETs)—a relatively rare disease with high prevalence—which has been constellated with numerous fundamental discoveries, many of which awarded the Nobel Prize. Specifically, NET imaging stems from the isolation of somatostatin from ovine hypothalamus by Paul Brazeau and Roger Guillemin in 1972 (later synthesized by Andrew V. Shally) and from the synthesis of octreotide, an analog capable of stability in plasma, in 1979. It then continues with the demonstration of overexpression of binding sites with high affinity for somatostatin in several NETs and culminates with the identification and cloning of the 5 somatostatin receptors in 1992 (2). In the same period, the group led by Eric P. Krenning at Erasmus University, Rotterdam, which included extraordinary teamwork by nuclear medicine and internal medicine physicians, endocrinologists, biologists, and radiochemists, with the collaboration of Jean-Claude Reubi, succeeded in radiolabeling octreotide. The idea at the basis of this endeavor was to exploit the internalizing and retention potential of the somatostatin analog octreotide to obtain in vivo binding and visualization of NETs. The obvious choice of radiolabel fell on the default imaging radionuclide at the time, 123I, which could be directly labeled to the Tyr3-substituted octreotide through the chloramine method. The first 10 patients studied with 123I-Tyr3-octreotide were announced in 1989 and constituted the first proof of principle of the value of somatostatin receptor imaging (3).
The disadvantages of scintigraphic imaging with the iodinated octreotide derivative were, however, immediately apparent: the difficult radiolabeling procedure, the cost and scarce availability of 123I worldwide, and, most importantly, the predominant biliary excretion, with substantial accumulation of the radiopeptide in the intestines, which complicated the interpretation of the very abdominal region involved by most NETs.
The group then developed an improved radiolabeled octreotide by replacing 123I with 111In. The different chemistry of this radionuclide required a chelating group, diethylenetriaminepentaacetic acid (DTPA), to be coupled to the amino-terminal of the first phenylalanine to form 111In-DTPA-d-Phe1-octreotide, which would later be named 111In-pentetreotide, or OctreoScan (Mallinckrodt). The new compound exhibited a more hydrophilic profile, with predominant renal excretion and only minimal biliary excretion. The longer half-life of 111In allowed for prolonged imaging times. The results for the first 26 patients studied by γ-camera scintigraphy, with a subgroup undergoing pharmacokinetics and dosimetry, were published in the seminal article “Somatostatin Receptor Scintigraphy with Indium-111-DTPA-D-Phe-1-Octreotide in Man: Metabolism, Dosimetry and Comparison with Iodine-123-Tyr-3-Octreotide” in 1992 (4). In these patients, 111In-DTPA-d-Phe1-octreotide provided optimal tumor visualization 24 h after injection, with comparable biodistribution (except for more intense uptake in the pituitary) and the capability for tumor localization to the original 123I-Tyr3-octreotide but improved visualization of the abdomen and target-to-background ratios due to the longer half-life of 111In. In addition, 111In-DTPA-d-Phe1-octreotide exhibited favorable pharmacokinetics (rapid plasma clearance and 85% urinary excretion at 24 h) and dosimetry (>70% of the effective-dose equivalent resulting from radioactivity in the kidneys, spleen, and liver). Multiphasic (4, 24, and 48 h) and SPECT imaging clearly improved the localization of lesions.
This 1992 work represented a milestone in NET management, was a paragon for the future development of theranostics based on radiolabeled receptor ligands, and marked the beginning of the era of somatostatin receptor imaging on a large scale. 111In-DTPA-d-Phe1-octreotide was, in fact, the first imaging radiopharmaceutical to receive Food and Drug Administration approval, in 1994. It was extensively used worldwide for the following 20 years, allowing for the localization, staging, and restaging of NETs and their metastases, as well as selection for treatment with somatostatin analogs.
111In-DTPA-d-Phe1-octreotide had formidable success and opened the way to the radionuclide treatment of advanced NETs, which the author group developed as the next logical step of the in vivo localization by exploiting the Auger emission of 111In administered in high activities (5). This approach initiated one of the most fortunate examples of theranostics, and a few decades and a few radionuclides later, it led the same group of authors to develop yet another radiopharmaceutical, 177Lu-DOTATATE, now approved for the treatment of metastatic or inoperable gastroenteropancreatic NETs (6).
However, just like our “Juggler of Day,” 111In-DTPA-d-Phe1-octreotide also had a decline. Despite the improvement resulting from SPECT/CT hybrid imaging, the diffusion of PET/CT on a large scale rendered this tracer, which had been the workhorse of NET imaging for over 2 decades, gradually obsolete. Its resolution limit and the frequent suboptimal visualization of the abdomen, due to intestinal activity, which required biphasic imaging, laxatives, and hydration, could not compare with the progressively more sophisticated CT and MR images. The availability of 68Ga-labeled compounds then marked the official decline of somatostatin receptor scintigraphy and the beginning of a new era. But this is a story for the next few decades…
DISCLOSURE
No potential conflict of interest relevant to this article was reported.
- © 2020 by the Society of Nuclear Medicine and Molecular Imaging.
REFERENCES
- Received for publication June 18, 2020.
- Accepted for publication June 26, 2020.