Cyclotron-based gallium-68 generator breaks production records

November 26, 2019 – Gallium-68 (68Ga) is a positron emitter that’s becoming established as a valuable diagnostic isotope, primarily for detection of neuroendocrine tumours (NETs). Such tumours do not metabolize glucose well – precluding their visualization via standard FDG-PET scans – but overexpress somatostatin receptors that bind, for example, to the PET agent 68Ga-Dotatate.

Currently, 68Ga is made using a germanium/gallium generator, in which 68Ga is created as its parent isotope 68Ge decays. Unfortunately, this approach only produces enough 68Ga for two or three patient scans per day. Canadian company ARTMS Products is developing an alternative technique, in which a low-energy cyclotron is used to create 68Ga from solid zinc-68 targets. The company has now demonstrated record breaking, multi-curie levels of 68Ga production.

“The primary challenge with germanium/gallium generators is that they can’t seem to make the generators fast enough, and when they do, the output is relatively limited,” explains Paul Schaffer, founder and CTO of ARTMS. “The generators make about one patient dose for each elution. So even if they run two or three per day, that’s only two or three patient doses per day, which is an expensive proposition for many centres.”

To address this problem, ARTMS developed the QUANTM Irradiation System (QIS), a 68Ga production scheme that includes enriched 68Zn targets, a transportation device that attaches onto the port of an existing medical cyclotron and a send-and-receive station that terminates inside a shielded workspace. Schaffer notes that the system is manufacturer-agnostic and can be installed on any major cyclotron brand.

The hardware enables a technician to load a non-radioactive 68Zn target into the transportation system. Automated pneumatics and robotics then move the target to the cyclotron’s target port, where it is irradiated for two hours by a proton beam. This proton irradiation generates 68Ga within the target via the 68Zn(p,n)68Ga nuclear reaction. The irradiated target is then brought back to the shielded space where the 68Zn can be extracted and purified for use in radiopharmaceuticals.

“What makes the ARTMS system unique is we’ve demonstrated that it can produce 68Ga at levels of 10 Ci – or 370 GBq,” says Schaffer. “This is 100 to 200 times more activity in a two-hour irradiation than a germanium/gallium generator can put out. This puts the problem not on the amount of gallium that you have but, with its 68 min half-life, the rush to use it all.”

He suggests that a hospital should to be able to produce about a day’s worth of 68Ga and scan several patients following a single cyclotron run. “And at the end of the day, you don’t have any 68Ge or long-lived by-products to deal with,” he notes.

The record-breaking 68Ga production was achieved at Odense University Hospital. The team there demonstrated multi-curie production of two radiopharmaceuticals: 68Ga-Dotatate (known as NETSPOT) and a prostate-specific membrane antigen (PSMA) radiopharmaceutical for imaging prostate cancer. The Odense team is now embarking on a validation study in preparation for regulatory submission.

“We have demonstrated the production level, we’ve demonstrated the chemistry and we’ve demonstrated that 68Ga quality is consistent with regulatory standards, but we have not yet received regulatory approval,” says Schaffer.

He explains that other centres worldwide are working with ARTMS to achieve regulatory approval for the QIS in their respective countries. “We have a system in Zurich and one in Wisconsin, and also have systems being installed in Japan, the UK, Costa Rica and Toronto,” he says. “I think it’s in everyone’s interest to get this approved as quick as possible.”

Schaffer notes that the new production technology is intended to supplement, rather than replace existing 68Ga generation methods. “There are going to be areas in the world that will continue to rely on reactor-produced isotopes. There will be areas where Ge-68 and Mo-99 generators just make sense,” he tells Physics World. “But there are many areas of the world that rely on cyclotron technology, and that’s where ARTMS wants to fit in, that’s our goal.”

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