Does gallium-citrate have yet another story to tell? Lessons relevant to the COVID-19 era

Excerpt

The evolution of [⁶⁷Ga]Ga-citrate as an imaging agent over the past three quarters of a century is fascinating from a historical point of view [1, 2]. Its storied saga recalls the formative years in the rise of nuclear medicine and many of the important diagnostic roles that scintigraphy played in the provision of health care over the past seven decades. [⁶⁷Ga]Ga-citrate was introduced at the time when mechanisms of localization of radiopharmaceuticals were rather opaque and choice of radiopharmaceuticals often proceeded by trial and error, if not by outright serendipity. Raymond Hayes has succinctly summarized this odyssey from a first-hand perspective [1]. In the late 1940s, non-radioactive gallium metal was being considered as a coolant for use in nuclear powered naval vessels which stimulated studies on the metal’s biodistribution. Utilizing the tracer principle, Dudley and coworkers determined that [⁷²Ga]Ga-citrate (and ionic gallium, in general) localized to a large degree at sites of osteogenesis [3, 4]; based on these findings, in the pre-technetium imaging agent era, there was interest in developing the radiopharmaceutical into a bone imaging, and potentially therapeutic, modality [5]. Gallium-72’s decay properties were eventually deemed insufficiently favorable for human use. Investigators at Oak Ridge and Bethesda subsequently turned their attention to [⁶⁷Ga]Ga-citrate, with its improved decay properties, but were chagrined to observe that the citrate ion of this radioisotope did not replicate the biodistribution seen with [⁷²Ga]Ga-citrate; they quickly realized that the disparity arose because of variation in specific (molar) activity of the radiopharmaceutical [6, 7]. Gallium-72, derived from reactor-production, contained chemically significant amounts of non-radioactive (“carrier”) gallium, while Gallium-67 was produced in a cyclotron and was “carrier free”, that is without addition of non-radioactive gallium atoms. Both radioisotopic forms of gallium-citrate were deemed not useful for bone imaging and were shelved for a decade. In the 1960s, investigators at Oak Ridge rekindled their interest in gallium as a means of bone imaging (including the possibility of addition of carrier gallium as needed), in part stimulated by new availability of Gallium-68. According to Hayes [1], the investigators were amazed to observe that carrier-free [⁶⁷Ga]Ga-citrate intensely localized in lymph nodes of a patient with Hodgkin’s disease [8], thereby laying the ground-work for what would subsequently become extensive use of carrier-free [⁶⁷Ga]Ga-citrate for clinical tumor imaging [9]. It was understood that ionic gallium in the blood was bound to circulating transferrin much in the way that iron is bound. Reliance on gallium scanning for lymphoma staging would prevail for decades, only waning in the 2000s when eclipsed by the novel radiopharmaceutical (D)-2-[¹⁸F]Fluoro-deoxy-glucose ([¹⁸F]FDG), coupled with widespread availability of PET-CT cameras [10]. …