Production and Use of the First-Row Transition Metal PET Radionuclides ^43,44Sc, ⁵²Mn, and ⁴⁵Ti

PRODUCTION OF ^43,44G,MSC

Recently, scandium nuclides have been of interest because of the potential therapeutic properties of ⁴⁷Sc, which can be combined with ^43,44gSc for imaging. An excellent review article describes the production routes of these 3 scandium isotopes using proton beams, α-particles, neutrons, and various target materials (2). ⁴³Sc (β⁺ = 88.1%, E_β+ = 476 keV) and ^44gSc (β⁺ = 94.3%, E_β+ = 632 keV) have half-lives of 3.89 and 3.97 h, respectively, (3). Although the 2 isotopes are similar, the main difference is the high-energy γ-ray (1.157 MeV, emitted 99.9% of the time) associated with ^44gSc. Additionally, ^44mSc, which is coproduced with ^44gSc, has a half-life of 58.6 h and has been suggested for use as an in vivo PET generator for ^44gSc (4). However, the longer half-life coupled with the high-energy γ-ray emitted from ^44gSc, may lead to unfavorable dosimetry for shorter studies.

Production routes for ^43,44g,m,47Sc use either calcium or titanium targets, typically enriched for the desired isotope. ⁴³Sc can be produced via proton irradiation of ⁴³Ca or ⁴⁶Ti, as well as α-irradiation of ⁴⁰Ca or deuteron irradiation of ⁴⁴Ca (5–7). ^44g,mSc can be produced via proton irradiation of ⁴⁴Ca, ⁴⁷Ti, or ⁴⁵Sc or deuteron irradiation of ⁴⁴Ca (2,4–20). Enriched targets are preferred to avoid production of contaminants such as ^46,48Sc (18). Production studies of ^44g,44mSc using deuterons yielded up to 90 MBq (4 h after the end of bombardment) with a 3-h bombardment (21). In a similar study, ^44g,44mSc was produced via deuteron irradiation of enriched ⁴⁴CaCO₃ targets, and the authors concluded that production of ^44g,mSc via calcium targets is preferable to ⁴³Sc because of the higher natural abundance of ⁴⁴Ca than of ⁴³Ca (7,22). Researchers have also studied the ⁴⁶Ti(p,α)⁴³Sc reaction and showed that this pathway produced ⁴³Sc of higher radionuclidic purity than when using the ⁴³Ca(p,n)⁴³Sc production route; however, the latter route produced ⁴³Sc in higher yields (18). Another source for ^44gSc is the ⁴⁴Ti/⁴⁴Sc generator (8,23). Although the generator method has been investigated, only a small number of facilities in the world have these generators in use.

Purification of ⁴³Sc is detailed in a recent report that included various methods by several researchers (9). This article described separation methods summarized in Table 1, all of which had favorable separation efficiency and recovery yields of more than 80% (9). Finally, another report detailed the separation of ^44gSc, showing recovery of up to 80% using H₂O as the final eluent on a UTEVA resin (Eichrom Technologies, LLC) (11). These methods for production and separation of ^43,44gSc enhance the availability of these nuclides for further development.

RADIOCHEMISTRY AND IMAGING OF ^43,44SC

^43,44gSc has been proposed as a matched-pair theranostic radioisotope that is a longer-lived alternative to ⁶⁸Ga for imaging analogs of ¹⁷⁷Lu. Scandium exists in the +3 oxidation state and is suitable for labeling of DOTA-derivatized biomolecules (24). In studies investigating ^44gSc as an imaging surrogate for ¹⁷⁷Lu, ^44gSc-labeled cm09 (DOTA-folate conjugate) was determined to have comparable properties, with pharmacokinetics nearly identical to the same compound labeled with ¹⁷⁷Lu (25).

However, using 2 different elements may create problems if they show different biodistributions. Radioscandium allows for the development of true matched-pair theranostics using chemically identical constructs as opposed to chemically similar constructs. In this case, the pair would be ^43,44gSc as the diagnostic agent and ⁴⁷Sc as the therapeutic agent. Studies have compared the labeling efficiencies of ⁶⁸Ga, ¹⁷⁷Lu, and ^44gSc for DOTA-HPMA (N-(2-hydroxypropyl) methacrylamide) conjugates and showed that the ^44gSc-labeled polymer was highly stable for up to 24 h, showing promising characteristics for in vivo imaging (12). A similar study determined that reaction rates were increased when buffers including EtOH were used, allowing for lower temperatures and a reduced time to achieve labeling yields above 90% for DOTA complexes with these 3 radioisotopes (26).

^44gSc was used to radiolabel DOTA-NAPamide for targeting of the melanocortin-1 receptor, with higher uptake in melanocortin-1 receptor–positive B16-F10 xenografts than in melanocortin-1 receptor–negative A375 xenografts (27). In another study, ^44gSc-DOTANOC was synthesized with high radiochemical yields and used for dynamic PET imaging, showing continuous uptake and high-quality images in AR42J tumor xenografts, encouraging the transition into clinical applications (24). A similar study optimized radiolabeling conditions for peptides such as DOTANOC and NODAGANOC with ^44gSc. After this, the authors determined that compounds labeled with ^44gSc had similar biodistribution to the same compounds labeled with ⁶⁸Ga except for a higher liver uptake seen in the latter (28). As these studies have indicated, ^43,44gSc shows promise for the development of matched-pair theranostic agents with ⁴⁷Sc.

PRODUCTION OF ⁵²MN

With a longer half-life of 5.6 d, a β⁺ branching ratio of 29.4%, and E_β+ of 242 keV, ^52gMn has characteristics complementary to the shorter-lived nuclides discussed and is a promising candidate for imaging of longer biologic processes or compounds that intrinsically contain manganese. However, ^52gMn emits multiple high-energy γ-rays, making work less favorable with ^52gMn than with some other radioisotopes (29). ^52gMn can be produced via the ⁵²Cr(p,x)^52gMn reaction, but radioisotope contaminants, including the long-lived ⁵⁴Mn, can be produced via the ⁵⁴Cr(p,n) reaction when natural chromium targets are used (27–29). Several groups have studied cross sections of these reactions to attain the highest yields with the fewest impurities (30,31). Various natural chromium target configurations have been studied, including metal targets, electrodeposition, and pressed powder targets (29,32,33). Targets have been irradiated with 16-MeV protons or less, because of the desirable cross section between 6 and 20 MeV, illustrating production of ⁵²Mn with low-energy cyclotrons (29,30,32–34).

Several separation methods have been developed for the purification of ^52gMn and are summarized in Table 2 (35,36). Although further optimization of the purification chemistry is required, these purification strategies have enabled the availability of this nuclide for research use.

RADIOCHEMISTRY AND IMAGING OF ⁵²MN

The radiochemistry of manganese has been deemed challenging because manganese and chromium have multiple oxidation states and because Mn(II) and Cr(III) behave similarly (32). Recent studies have noted that ^52gMn can be chelated with EDTA, DTPA, and DOTA, with straightforward labeling chemistry similar to radionuclides of scandium previously discussed (36).^52gMn has been used in several imaging applications. For example, recent studies showed that Mn²⁺ can enter neurons, and thus, ^52gMn has been studied as a neural imaging agent (37). Because manganese is also used as a contrast agent in manganese-enhanced MRI, MRI tools can benefit from the use of ^52gMn to enhance the understanding of the pharmacokinetics of these agents (38). An excellent example of using ^52gMn for dual PET/MRI made use of Mn²⁺ for manganese-enhanced MRI and ^52gMn for PET imaging studies on neural progenitor cells that overexpress divalent metal transporter 1 (32). Researchers found that the effectiveness of cell therapy could be measured using the dual-modality PET/MRI method by applying divalent metal transporter 1 as a reporter gene (32). In another study, the use of ^52gMn coupled with a DOTA antibody conjugate (DOTA-TRC105) for PET imaging of mice bearing 4T1 xenografts was reported (34). That study showed that ^52gMn can be used as a PET agent for imaging time points of up to 120 h and resulted in high-quality images as shown in Figure 1. Although DOTA-coupled compounds can be labeled with both ^52gMn and ^43,44gSc, the application is important for radionuclide selection, with the former having longer imaging times and the latter being used for the development of true theranostics (28).

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FIGURE 1.

Results of ⁵²Mn-DOTA-TRC105 injection into 4T1 xenograft tumor–bearing mice. %ID = percentage injected dose. (Reprinted with permission from (34).)

Another interesting study showed the uptake of ^52gMn-Mn²⁺ in monkeys after nostril administration of the radiotracer (37). Brain uptake in rhesus macaque monkeys was determined over 8 sessions with at least 6 mo between each session. After 7 d, activity was seen in parts of the brain after following the olfactory tract, which demonstrated that ^52gMn-Mn²⁺ can be used to for neuronal imaging (39). ^52gMn-Mn(oxinate)₂ was synthesized and determined to have suitable in vitro stability to study extravasation in vivo when conjugated with a liposomal nanomedicine (40). In another study, which leveraged the biologic properties of Mn²⁺, ^52gMn²⁺-Mn²⁺ was successfully used to image functional β-cell mass in mice with type 1 and type 2 diabetes (41). Finally, ^52gMn²⁺-Mn²⁺ was used to investigate the biodistribution of manganese when administered intravenously or through inhalation (38). That study found most organs to have higher uptake when the dose was administered intravenously, with the highest uptake being in the kidney and liver (38). In summary, the implementation of ^52gMn could provide a new way to image long-circulating compounds and to enhance the results from manganese MRI tools.

PRODUCTION OF ⁴⁵TI

⁴⁵Ti has many favorable characteristics for PET imaging, including a naturally monoisotopic target material, a half-life of 3.08 h, low maximum positron energy (E_β+ = 439 keV), and a high positron branching ratio (β⁺ = 84.8%). Compared with the previous nuclides discussed, ⁴⁵Ti production may be the most economical. Although not heavily studied to date, recent articles showed the utility of ⁴⁵Ti. ⁴⁵Ti is produced via proton bombardment of natural scandium foils through the ⁴⁵Sc(p,n)⁴⁵Ti reaction. Promising results were achieved using 11.8-MeV protons to avoid production of the long-lived ⁴⁴Ti (42). An excellent review article has described the historical interest and significance of ⁴⁵Ti, as well as some of the most recent advances in its production and separation methods (43). For the purification of ⁴⁵Ti, studies have used hydroxamate resin with reported yields of up to 42% ± 6%, with a separation time of an hour (42). Production yields of 4.6 ± 0.4 GBq (20 μA,11.8-MeV protons, 1 h) have been reported, compared with previously calculated theoretic yields of 2.165 GBq (5 μA, 14.5-MeV protons, 1 h) (42,44–46). A novel separation method achieved 93% ± 3% recovery via use of a HypoGel 200 (Rapp Polymere GmbH) 1,3-diol resin to retain ⁴⁵Ti on the column and then subsequently introduced salan followed by dipic in pyridine for radiolabeling on the same column, to produce ⁴⁵Ti-(salan)Ti(dipic) (47). These production parameters indicate that ⁴⁵Ti can be readily produced in significant quantities using low-cost target material.

RADIOCHEMISTRY AND IMAGING OF ⁴⁵TI

Radiochemistry with ⁴⁵Ti, which exists in the +3 and +4 oxidation states, is challenging because of the potential oxidation of Ti to TiO_2, its instability in an aqueous environment, and the challenge of finding stable titanium chelators (47). Researchers illustrated that ⁴⁵Ti could be used to radiolabel mesoporous silica nanoparticles using a chelator-free radiolabeling technique (42). In another study using an on-column radiolabeling technique, the radiolabeled antitumor agent ⁴⁵Ti-(salan)Ti(dipic) was applied for PET/CT imaging and biodistribution studies and showed rapid clearance from blood and liver, whereas the uptake in the tumor remained constant for 400 min (47). Previous studies showed that ⁴⁵Ti could be used to radiolabel apotransferrin, which forms a complex that remains intact in vivo, demonstrating transport of ⁴⁵Ti to tumors for 24 h after injection (48). ⁴⁵Ti can yield high-resolution images as illustrated with recent phantom imaging studies in our group. Figure 2 shows a miniature Derenzo phantom imaged with 3.7 MBq of ⁴⁵Ti on the small-animal PET scanner at the University of Alabama at Birmingham. When isotopes with moderate half-lives are compared, ⁴⁵Ti and ^43,44gSc are comparable; however, the straightforward production may make ⁴⁵Ti more appealing as a diagnostic radionuclide if chemistry challenges can be overcome.

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FIGURE 2.

Miniature Derenzo phantom image (3.7 MBq of ⁴⁵Ti; image taken after 60-min scan time).

DISCLOSURE

No potential conflict of interest relevant to this article was reported.