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. 2023 Aug 13;28(16):6041.
doi: 10.3390/molecules28166041.

Accelerator-Based Production of Scandium Radioisotopes for Applications in Prostate Cancer: Toward Building a Pipeline for Rapid Development of Novel Theranostics

Jason P Meier  1 , Hannah J Zhang  1   2 , Richard Freifelder  1   3   4 , Mohammed Bhuiyan  1   3 , Phillip Selman  5 , Megan Mendez  5 , Pavithra H A Kankanamalage  6   7 , Thomas Brossard  6 , Antonino Pusateri  1 , Hsiu-Ming Tsai  2 , Lara Leoni  2 , Sagada Penano  1 , Kaustab Ghosh  1   3 , Brittany A Broder  1   8 , Erica Markiewicz  2 , Amy Renne  1   6 , Walter Stadler  4   5 , Ralph Weichselbaum  4   9 , Jerry Nolen  4   6 , Chien-Min Kao  1   2   4 , Satish K Chitneni  1 , David A Rotsch  4   6   10 , Russell Z Szmulewitz  4   5 , Chin-Tu Chen  1   2   3   4
Affiliations

Accelerator-Based Production of Scandium Radioisotopes for Applications in Prostate Cancer: Toward Building a Pipeline for Rapid Development of Novel Theranostics

Jason P Meier et al. Molecules. .

Abstract

In the field of nuclear medicine, the β+ -emitting 43Sc and β- -emitting 47Sc are promising candidates in cancer diagnosis and targeted radionuclide therapy (TRT) due to their favorable decay schema and shared pharmacokinetics as a true theranostic pair. Additionally, scandium is a group-3 transition metal (like 177Lu) and exhibits affinity for DOTA-based chelators, which have been studied in depth, making the barrier to implementation lower for 43/47Sc than for other proposed true theranostics. Before 43/47Sc can see widespread pre-clinical evaluation, however, an accessible production methodology must be established and each isotope's radiolabeling and animal imaging capabilities studied with a widely utilized tracer. As such, a simple means of converting an 18 MeV biomedical cyclotron to support solid targets and produce 43Sc via the 42Ca(d,n)43Sc reaction has been devised, exhibiting reasonable yields. The NatTi(γ,p)47Sc reaction is also investigated along with the successful implementation of chemical separation and purification methods for 43/47Sc. The conjugation of 43/47Sc with PSMA-617 at specific activities of up to 8.94 MBq/nmol and the subsequent imaging of LNCaP-ENZaR tumor xenografts in mouse models with both 43/47Sc-PSMA-617 are also presented.

Keywords: PET; PSMA-617; SPECT; Scandium-43; Scandium-47; TRT; mCRPC; prostate cancer; radioisotopes; theranostics.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Certain commercial equipment, instruments, or materials are identified in this paper to foster understanding. Such identification does not imply recommendation by the authors or their affiliated institutions, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose.

Figures

Figure 1
Figure 1
Schematic drawing of the target holder showing the backing disk and the ring that is joined to the backing to hold the 42Ca powder. The holder’s location within the beam stop is marked in blue, also exemplifying that the target-holder insert is loaded from the front of the beam stop (i.e., where the beam enters the beam stop when inserted) and cooling is provided by the back of the beam stop along the edges of the stepped cone.
Figure 2
Figure 2
Photographs of the target holder and a representative 42CaO target.
Figure 3
Figure 3
A logarithmic γ-spectrum of 43Sc taken from the solid target and graphite foils acquired one hour after the end of bombardment at 30.48 cm using a RayMon 10 handheld CZT detector.
Figure 4
Figure 4
Activity at the end of bombardment for each 43Sc production run along with the theoretically estimated activity from the numerical solving of Equation (1).
Figure 5
Figure 5
The percent difference of the experimentally obtained 43Sc yields relative to the numerically estimated yields as a function of target mass.
Figure 6
Figure 6
A representative natural titanium target utilized in the production of 47Sc.
Figure 7
Figure 7
Logarithmically scaled γ-spectrum data of 47Sc taken from the solid target and foil taken after elution from the DGA column with HCl.
Figure 8
Figure 8
Representative iTLC of 43Sc-PSMA-617. The absence of a peak near the origin of the iTLC exhibits the successful radiolabeling of 43Sc-PSMA-617 with a yield of > 95%.
Figure 9
Figure 9
Representative HPLC chromatogram of 43Sc-PSMA-617. The proximity of the retention times of the UV trace of cold PSMA-617 (bottom) and the radioactive trace of the solutions of radiolabeled 43Sc-PSMA-617 and (top) indicate successful radiolabeling.
Figure 10
Figure 10
Representative iTLC of 47Sc-PSMA-617. The absence of a peak near the origin of the iTLC exhibits the successful radiolabeling of 47Sc-PSMA-617 with a yield of > 95%.
Figure 11
Figure 11
Representative HPLC chromatogram of 47Sc-PSMA-617. The proximity of the retention times of the UV trace of cold PSMA-617 (bottom) and the radioactive trace of the solutions of radiolabeled 47Sc-PSMA-617 and (top) indicate successful radiolabeling.
Figure 12
Figure 12
RadioHPLC chromatograms from 1, 24, and 48 h time-points for 43Sc-PSMA-617. As no additional peaks are observed beyond the main radiolabeled 43Sc-PSMA-617 peaks, it can be concluded that the compound is stable in PBS. Decreasing peak size is the result of radioactive decay.
Figure 13
Figure 13
RadioHPLC chromatograms from 1, 24, and 48 h time-points for 47Sc-PSMA-617. As no additional peaks are observed beyond the main radiolabeled 47Sc-PSMA-617 peaks, it can be concluded that the compound is stable in PBS. Decreasing peak size is the result of radioactive decay.
Figure 14
Figure 14
Representative images of the LNCaP-EnzaR animal model taken with 43Sc PET (a) and 47Sc SPECT (b) at 2 h post-injection. The arrows in each figure point to the xenografted LNCaP-ENZaR tumor.
See this image and copyright information in PMC

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