Measurement of 43Sc and 44Sc production cross-section with an 18MeV medical PET cyclotron.

43Sc and 44Sc are positron emitter radionuclides that, in conjunction with the ß- emitter 47Sc, represent one of the most promising possibilities for theranostics in nuclear medicine. Their availability in suitable quantity and quality for medical applications is an open issue and their production with medical cyclotrons represents a scientific and technological challenge. For this purpose, an accurate knowledge of the production cross sections is mandatory. In this paper, we report on the cross section measurement of the reactions 43Ca(p,n)43Sc, 44Ca(p,2n) 43Sc, 46Ti(p,α)43Sc, and 44Ca(p,n)44Sc at the Bern University Hospital cyclotron. A study of the production yield and purity performed by using commercially available enriched target materials is also presented.

Imaging quality of (44)Sc in comparison with five other PET radionuclides using Derenzo phantoms and preclinical PET.

PET is the favored nuclear imaging technique because of the high sensitivity and resolution it provides, as well as the possibility for quantification of accumulated radioactivity. (44)Sc (T1/2=3.97h, Eß(+)=632keV) was recently proposed as a potentially interesting radionuclide for PET. The aim of this study was to investigate the image quality, which can be obtained with (44)Sc, and compare it with five other, frequently employed PET nuclides using Derenzo phantoms and a small-animal PET scanner. The radionuclides were produced at the medical cyclotron at CRS, ETH Zurich ((11)C, (18)F), at the Injector II research cyclotron at CRS, PSI ((64)Cu, (89)Zr, (44)Sc), as well as via a generator system ((68)Ga). Derenzo phantoms, containing solutions of each of these radionuclides, were scanned using a GE Healthcare eXplore VISTA small-animal PET scanner. The image resolution was determined for each nuclide by analysis of the intensity signal using the reconstructed PET data of a hole diameter of 1.3mm. The image quality of (44)Sc was compared to five frequently-used PET radionuclides. In agreement with the positron range, an increasing relative resolution was determined in the sequence of (68)Ga<(44)Sc<(89)Zr<(11)C<(64)Cu<(18)F. The performance of (44)Sc was in agreement with the theoretical expectations based on the energy of the emitted positrons.

Cyclotron production of (44)Sc: From bench to bedside.

INTRODUCTION: (44)Sc, a PET radionuclide, has promising decay characteristics (T1/2 = 3.97 h, Eß(+)av = 632 keV) for nuclear imaging and is an attractive alternative to the short-lived (68)Ga (T1/2 = 68 min, Eß(+)av = 830 keV). The aim of this study was the optimization of the (44)Sc production process at an accelerator, allowing its use for preclinical and clinical PET imaging. METHODS: (44)CaCO3 targets were prepared and irradiated with protons (~11 MeV) at a beam current of 50 µA for 90 min. (44)Sc was separated from its target material using DGA extraction resin and concentrated using SCX cation exchange resin. Radiolabeling experiments at activities up to 500 MBq and stability tests were performed with DOTANOC by investigating different scavengers, including gentisic acid. Dynamic PET of an AR42J tumor-bearing mouse was performed after injection of (44)Sc-DOTANOC. RESULTS: The optimized chemical separation method yielded up to 2 GBq (44)Sc of high radionuclidic purity. In the presence of gentisic acid, radiolabeling of (44)Sc with DOTANOC was achieved with a radiochemical yield of ~99% at high specific activity (10 MBq/nmol) and quantities which would allow clinical application. The dynamic PET images visualized increasing uptake of (44)Sc-DOTANOC into AR42J tumors and excretion of radioactivity through the kidneys of the investigated mouse. CONCLUSIONS: The concept "from-bench-to-bedside" was clearly demonstrated in this extended study using cyclotron-produced (44)Sc. Sufficiently high activities of (44)Sc of excellent radionuclidic purity are obtainable for clinical application, by irradiation of enriched calcium at a cyclotron. This work demonstrates a promising basis for introducing (44)Sc to clinical routine of nuclear imaging using PET.

Promising prospects for 44Sc-/47Sc-based theragnostics: application of 47Sc for radionuclide tumor therapy in mice.

UNLABELLED: In recent years, (47)Sc has attracted attention because of its favorable decay characteristics (half-life, 3.35 d; average energy, 162 keV; Eγ, 159 keV) for therapeutic application and for SPECT imaging. The aim of the present study was to investigate the suitability of (47)Sc for radionuclide therapy in a preclinical setting. For this purpose a novel DOTA-folate conjugate (cm10) with an albumin-binding entity was used. METHODS: (47)Sc was produced via the (46)Ca(n,γ)(47)Ca[Formula: see text](47)Sc nuclear reaction at the high-flux reactor at the Institut Laue-Langevin. Separation of the (47)Sc from the target material was performed by a semi-automated process using extraction chromatography and cation exchange chromatography. (47)Sc-labeled cm10 was tested on folate receptor-positive KB tumor cells in vitro. Biodistribution and SPECT imaging experiments were performed in KB tumor-bearing mice. Radionuclide therapy was conducted with two groups of mice, which received either (47)Sc-cm10 (10 MBq) or only saline. Tumor growth and survival time were compared between the two groups of mice. RESULTS: Irradiation of (46)Ca resulted in approximately 1.8 GBq of (47)Ca, which subsequently decayed to (47)Sc. Separation of (47)Sc from (47)Ca was obtained with 80% yield in only 10 min. The (47)Sc was then available in a small volume (∼500 µL) of an ammonium acetate/HCl (pH 4.5) solution suitable for direct radiolabeling. (47)Sc-cm10 was prepared with a radiochemical yield of more than 96% at a specific activity of up to 13 MBq/nmol. In vitro (47)Sc-cm10 showed folate receptor-specific binding and uptake into KB tumor cells. In vivo SPECT/CT images allowed the visualization of accumulated radioactivity in KB tumors and in the kidneys. The therapy study showed a significantly delayed tumor growth in mice, which received (47)Sc-cm10 (10 MBq, 10 Gy) resulting in a more than 50% increase in survival time, compared with untreated control mice. CONCLUSION: With this study, we demonstrated the suitability of using (47)Sc for therapeutic purposes. On the basis of our recent results obtained with (44)Sc-folate, the present work confirms the applicability of (44)Sc/(47)Sc as an excellent matched pair of nuclides for PET imaging and radionuclide therapy.

Future prospects for SPECT imaging using the radiolanthanide terbium-155 - production and preclinical evaluation in tumor-bearing mice.

INTRODUCTION: We assessed the suitability of the radiolanthanide (155)Tb (t1/2=5.32 days, Eγ=87 keV (32%), 105keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging. METHODS: (155)Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (~1.4 GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. (155)Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules - a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) - were radiolabeled with (155)Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner. RESULTS: The total yield of the two-step separation process of (155)Tb was 86%. (155)Tb was obtained in a physiological l-lactate solution suitable for direct labeling processes. The (155)Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (>95%). (155)Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of (155)Tb-DOTATATE and (155)Tb-MD, respectively. The relatively long physical half-life of (155)Tb matched in particular the biological half-lives of (155)Tb-cm09 and (155)Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration. CONCLUSIONS: The radiolanthanide (155)Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the ß(-)-emitting radiolanthanides (177)Lu, (161)Tb, (166)Ho, and the pseudo-radiolanthanide (90)Y.

Promises of cyclotron-produced 44Sc as a diagnostic match for trivalent ß--emitters: in vitro and in vivo study of a 44Sc-DOTA-folate conjugate.

UNLABELLED: In recent years, implementation of (68)Ga-radiometalated peptides for PET imaging of cancer has attracted the attention of clinicians. Herein, we propose the use of (44)Sc (half-life = 3.97 h, average ß(+) energy [Eß(+)av] = 632 keV) as a valuable alternative to (68)Ga (half-life = 68 min, Eß(+)av = 830 keV) for imaging and dosimetry before (177)Lu-based radionuclide therapy. The aim of the study was the preclinical evaluation of a folate conjugate labeled with cyclotron-produced (44)Sc and its in vitro and in vivo comparison with the (177)Lu-labeled pendant. METHODS: (44)Sc was produced via the (44)Ca(p,n)(44)Sc nuclear reaction at a cyclotron (17.6 ± 1.8 MeV, 50 µA, 30 min) using an enriched (44)Ca target (10 mg (44)CaCO3, 97.00%). Separation from the target material was performed by a semiautomated process using extraction chromatography and cation exchange chromatography. Radiolabeling of a DOTA-folate conjugate (cm09) was performed at 95°C within 10 min. The stability of (44)Sc-cm09 was tested in human plasma. (44)Sc-cm09 was investigated in vitro using folate receptor-positive KB tumor cells and in vivo by PET/CT imaging of tumor-bearing mice RESULTS: Under the given irradiation conditions, (44)Sc was obtained in a maximum yield of 350 MBq at high radionuclide purity (>99%). Semiautomated isolation of (44)Sc from (44)Ca targets allowed formulation of up to 300 MBq of (44)Sc in a volume of 200-400 µL of ammonium acetate/HCl solution (1 M, pH 3.5-4.0) within 10 min. Radiolabeling of cm09 was achieved with a radiochemical yield of greater than 96% at a specific activity of 5.2 MBq/nmol. In vitro, (44)Sc-cm09 was stable in human plasma over the whole time of investigation and showed folate receptor-specific binding to KB tumor cells. PET/CT images of mice injected with (44)Sc-cm09 allowed excellent visualization of tumor xenografts. Comparison of cm09 labeled with (44)Sc and (177)Lu revealed almost identical pharmacokinetics. CONCLUSION: This study presents a high-yield production and efficient separation method of (44)Sc at a quality suitable for radiolabeling of DOTA-functionalized biomolecules. An in vivo proof-of-concept study using a DOTA-folate conjugate demonstrated the excellent features of (44)Sc for PET imaging. Thus, (44)Sc is a valid alternative to (68)Ga for imaging and dosimetry before (177)Lu-radionuclide tumor therapy.