Compelling Case for Fostering Titanium-45 for Positron Emission Tomography Tracer Applications

Gallium-68

The generator-based availability of ⁶⁸Ga, which is surely an advantage, has however led to a monopoly hold by ⁶⁸Ge-⁶⁸Ga vendors, including through their influence on the limited number of ⁶⁸Ge (271 days) producers. Naturally, this has led to researchers exploring alternate options for ⁶⁸Ga, given the growing number of MC available around the world. A consequential success recently reported is in terms of the daily production and supply of ⁶⁸Ga produced by ⁶⁸Zn (p, n) reaction in MC in curie (GBq) level, as well as the scope to use both solid and liquid (enriched) targets of ⁶⁸Zn. This is an important milestone in NM and was specifically highlighted in the International Atomic Energy Agency (IAEA) event “International Symposium on Trends in Radiopharmaceuticals (ISTR-2019)” by many groups.[12] For example, up to 140 GBq of ⁶⁸Ga was produced following 90-min irradiation of pressed powder target of ⁶⁸Zn. The overall recovery yield of ⁶⁸GaCl₃ was 89% with 77 ± 5 GBq/μmol at the end of bombardment.[1] A group from Portugal reported a liquid target system for ⁶⁸Ga production and is in daily use for curie-level production and supply.[12]

Titanium-45

In view of the above fruitful development, a natural poser can be: Is there an alternate, or supplement, to the direct production of the PET tracer ⁶⁸Ga in MC? Based on the literature available and certain recent publications and presentations, it is envisaged that the positron emitter ⁴⁵Ti can eminently meet such a need.[123] ⁴⁵Ti has a half-life of 3.08 h, 85% decay by positron emission (rest 15% by electron capture), and a β⁺ end-point energy of 1.04 MeV. More importantly, the target required for its production is natural scandium, a mononuclidic element (⁴⁵Sc). The reported cross-section for the ⁴⁵Sc (p, n) ⁴⁵Ti reaction is in the range of 200–400 mb depending on incident energy, Ep 12–14 MeV. At the University of Alabama, Birmingham, USA, 18 MeV MC was used with an energy degradation Al foil; typical yield reported (1): ⁴⁵Sc(p, n) ⁴⁵Ti, Ep 13–14 MeV, 0.5 h, 10 μA, 63 mCi (2.35 GBq). Irradiation for an hour with 50 μA current will result in 23.5 GBq production of ⁴⁵Ti, a substantial quantity for regular use. The existing distribution schemes worked out for ¹⁸F products; ¹⁸F-FDG, in particular, will be adoptable for the supply of ⁴⁵Ti, for both intra-city and inter-city supplies.

It is required to ensure that the right energy of incident protons is used so as to avoid (p, 2n) reaction on ⁴⁵Sc, which will result in the production of traces of long-lived ⁴⁴Ti (60 years). Further, the envisaged short duration of MC irradiation of ⁴⁵Sc target, namely, about an hour or two, will also help minimize the formation of traces of long-lived ⁴⁴Ti. Thus, naturally, ⁴⁵Ti production deserves much attention by every MC facility, including in India, which has already a suitable solid target station (e.g., SGPGIMS, Lucknow; INMAS, Delhi; and Cycone-30 of VECC-BRIT, Kolkata), or where it may be possible to install one. It is necessary to also encourage the direct production of ⁶⁸Ga from enriched ⁶⁸Zn target, despite the logistics challenges due to its 68-min half-life. Wherever ⁴⁵Ti can be used in the place of ⁶⁸Ga, it should be encouraged, as it will reduce the requirement of ⁶⁸Ga to that extent.

Demands on MC industry will accordingly change with the requirement of solid target stations to be an essential part of new MC establishments, in order to enable the production of many radioisotope (RI) (e.g., ⁶⁴Cu, ⁶⁸Ga, and ⁸⁹Zr) of emerging importance, including ⁴⁵Ti. MC of Ep >13 MeV energy (variable, preferably) would be in demand, for adopting the required reaction options for more RI production, i.e., MC of 10–11 MeV is no more likely to be attractive. The simplicity of compact, fixed-energy proton accelerator – cyclotron – has to make way for needs-based alterations/additions, to avail of the required incident energy of projectiles on the target(s) for medical RI production.

⁴⁵Ti radiopharmaceuticals

There has been interest in ⁴⁵Ti product reported even in 2005.[4] The chemistry of gallium and titanium is not identical; also, titanium is more prone to hydrolysis in certain conditions. Although this may be held against ⁴⁵Ti, especially for the theranostic approach, where the pair of ⁶⁸Ga and ¹⁷⁷Lu has got so well established, radiopharmacists and allied scientists have adequate expertise and scope to develop suitable new products of ⁴⁵Ti for potential clinical use. The recent review by Costa et al. is deemed an important literature in this context.[3] One can cite first the high interest and clinical importance in PET tracer-based high-resolution imaging of infection and of myocardial perfusion (MPI), the latter aided further by the superior quantification advantage of PET technique. Development of PET products for such use will be a much welcome addition, for example, one can explore ⁴⁵Ti- ubiquicidine (UBI) fragment for infection imaging (akin ⁶⁸Ga-UBI and ^99mTc-UBI). Many ligands (e.g., acetylacetone, nioxime) studied or used with ^99mTc could be similarly potential candidates for developing ⁴⁵Ti-based MPI agents (e.g., [Ti (L) ₃]⁺ type). The early launch of one or more such product will give a big thrust to PET-based nuclear cardiology.

This is not to say that ⁴⁵Ti cannot be used for peptide-like binder-based radiopharmaceutical for targeted tumor imaging. Both known chelators and novel ones are possible for using with ⁴⁵Ti and conjugation to a specific binder moiety, for example, peptide, antibody, and enzyme inhibitor to target tumors and other lesions, which present the corresponding binding site, for example, receptor and antigen, overexpressed on the tumors. Deferoxime is currently the chelator being used with another longer lived PET tracer ⁸⁹Zr (3.27 days, 22.3% positron emission; also producible from natural target ⁸⁹Y),[12] and it can be a good starting point for ⁴⁵Ti too (due to the similarity of M (IV) chemistry).

Concluding remarks (Please see footnote)

This brief note (Commentary) is aimed at triggering multipronged R&D efforts by willing researchers and their institutions, including through harnessing synergies and collaborations, to strive to pragmatically expand the inventory of easy-to-access ⁴⁵Ti-based PET radiopharmaceuticals of clinical utility. The IAEA has been requested to consider supporting such measures, for example, through a Coordinated Research Project (CRP).[2] These will help to effectively supplement and complement the growing use of ⁶⁸Ga-based PET tracers, apart from signaling the end of vulnerability to the undesirable monopoly effect of some vendors!

Footnote text

For performing exploratory studies on titanium-based products for potential medical use, one can use as a starting point, the long-lived ⁴⁴Ti (60 d) producible by (p,2n) reaction on ⁴⁵Sc target in a suitable cyclotron on a campaign mode, and/or use the very short-lived ⁵¹Ti (5.76 min; not carrier-free) producible repeatedly in fairly good quantity using a suitable neutron source, including a reactor, where available/accessible.

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Conflicts of interest

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