The Transition from Non-Metallic to Metallic Radioisotopes

The utilisation of nuclear imaging for early therapeutic intervention and personalised medicine is well established. Nuclear imaging relies on unique molecules, referred to as molecular probes, that track changes at the molecular level due to the disease. Molecular probes, tagged with radioisotopes, generate signals that subsequently get converted into scans. These scans are a crucial input for the treatment of the disease.

In the past few decades, India has seen an upsurge in the establishment of nuclear medicine centres. Of the 349 established centres as of February 2020, only a handful actively engage in research on novel molecular probes. Amongst these is the Institute of Nuclear medicine and Allied Sciences (INMAS). Established in 1961, INMAS was primarily a thyroid treatment and cancer research centre until the installation of a medical cyclotron.

With the advent of the cyclotron, the Institute was able to develop and produce several radio isotopes which could be tagged to molecular probes for nuclear imaging. The initial focus after the installation of the cyclotron was on the use of non-metallic radioisotopes such as the widely used Fluorine-18 as well as Carbon-11, Nitrogen-13 and Oxygen-15.

A critical challenge with the Fluorine-18 is its extremely short half-life of 110 minutes. The short half-life constrains the distance to which the isotope could be transported from the production facility of the isotope to the imaging centre. If there is no production facility in the vicinity of the imaging centre, the probe will become inactive by the time it reaches the imaging centre.

In large cities with adequate infrastructure, the short half-life would not matter, as manufacturing units of isotopes as well as imaging centres exist in the vicinity of each other. However, in large parts of India, which still has limited infrastructure, the imaging centres exist, but there are few facilities for developing the radio isotope.

The solution lies in switching from Fluorine-18 to other radioisotopes without compromising on the quality of the imaging. A crucial breakthrough in this direction would be to move away from non-metallic to metallic isotopes. Metal radioisotopes offer several advantages over non-metallic radioisotopes. First, these metal radioisotopes have a prolonged half-life, thereby doing away with the binding constraint of close proximity of imaging centres to  health care facilities.  Second, in addition to being used for diagnostics, these class of radioisotopes are also used for therapy. By using the same isotope for radiation and therapy, the degrees of uncertainty associated with dosage and targeting are reduced. This could potentially overcome the subtle modifications in the behaviour of biological systems exposed to different molecules for therapy and diagnosis. The application of metal radioisotopes can prove beneficial while planning diagnosis and therapy or put simply, in the design of theranostic agents (therapeutic and diagnostic).

Amongst the metallic radioisotope candidates, Scandium is one of the most promising. With its significantly higher half-life of 3.9 hours as compared to Fluorine-18 (110 min) and therapeutic isotopes such as Scandium-47 (β–particle emitter, half-life 3.35 days) it can serve as a theranostic matched pair. However, a critical challenge is the production of Scandium at scale for clinical application.

Professor Roger Schibli and his team, including Dr Christiaan Vermeulen and Dr Nick van der Meulen, from the Paul Scherrer Institute (PSI) reported breakthroughs in the production of scandium radioisotopes using a cyclotron. This provided a useful entry point for collaborative research for INMAS. The Indo-Swiss Joint Research Programme, co-funded by the two Governments, provided a platform for collaboration between the teams of INMAS and PSI. This collaboration led to the trial production of Scandium-44 for the first time in India using 16.5 MeV medical cyclotron housed at INMAS by irradiation of calcium carbonate. This was followed by isolating Scandium-44 using the extraction and purification protocol developed at PSI. The plan is to use Scandium-44 to label the natural hormone somatostatin analogue, the octreotate. Radiolabelled octreotate will specifically bind to the neuroendocrine tumours expressing somatostatin receptors.

Our collaborative R&D bodes well for the future development of domestic capabilities in the production and use of metallic radioisotopes, in particular Scandium, for theranostics in India. In particular, it provides the opportunity to scale up production of Scandium-44 and to develop methods for other therapeutic radioisotopes. The knowledge gained while implementing the project will lay the foundation of strengthened partnerships with state-of-the-art research institutions around the world. Our firm belief is that this fundamental effort has contributed to the technological capabilities, enabling long term partnerships.