PRODUCTION OF 43SC RADIONUCLIDE AND ITS USE IN POSITRON EMISSION TOMOGRAPHY

Abstract

The radionuclide 43Sc is produced at commercially significant yields and at specific activities and radionuclidic purities which are suitable for use in radiodiagnostic agents including imaging agents. In a method, a solid target having an isotopically enriched target layer prepared on an inert substrate is positioned in a specially configured target holder and irradiated with a charged-particle beam of protons or deuterons. The beam is generated using an accelerator such as a biomedical cyclotron at energies ranging from 3 to about 22. MeV. The method includes the use of three different nuclear reactions: a) irradiation of enriched 43Ca targets with protons to generate the radionuclide 43Scin the nuclear reaction 43Ca (p,n)43Sc, b) irradiation of enriched 42Ca targets with deuterons to generate the radionuclide 43Sc in the nuclear reaction 42Ca(d,n)43Sc, and c) irradiation of enriched 46Ti targets with protons to generate the radionuclide 43Sc in the nuclear reaction 46Ti (p,a) 43Sc.

Claims

1. A radiopharmaceutical to be applied in positron emission tomography, comprising: a radiometal-based radiopharmaceutical agent containing a bifunctional chelator namely a DOTA ligand (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) conjugated to a targeting vector and 43Sc being bound to a chelating agent.

2. The radiopharmaceutical according to claim 1, wherein said targeting vector is selected from the group consisting of an antibody, a peptide, nanoparticles, a vitamin and their derivates.

3. A radiopharmaceutical, comprising: a dose for one positron emission tomography having 43Sc to a radio content of 100 to 500 MBq.

4. The radiopharmaceutical according to claim 3, wherein said radio content is about 200 MBq.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

[0036] FIG. 1 shows, schematically, a possible target design showing the position and relative thickness of the target material after pressing together with the graphite powder; and

[0037] FIG. 2 shows a schematic diagram of the .sup.43Sc production panel using enriched Ca.

DETAILED DESCRIPTION OF THE INVENTION

[0038] In search for such a longer-lived, positron-emitting radionuclide, the present invention identifies 43Sc as a more appropriate candidate than 68Ga, with chemical properties more similar to Y and the lanthanides and, thus, a more appropriate match than its Ga counterpart. The radioactive decay of .sup.43Sc occurs with a low average positron energy of 0.476 MeV (68Ga: 0.830 MeV), a high total positron yield of 88.1% (68Ga: 88.9%), and an ideal half-life of 3.89 h (68Ga: 1.13 h), thereby, allowing its transport over long distances to the costumer (i.e. >500 km). Its decay is associated with a relatively low energy gamma-ray of 373 keV and 23% abundance (68Ga: 1077 keV, 3.2%), which will not influence PET imaging negatively, as modern PET scanners can be operated using a relatively narrow energy window (i.e. 440-665 keV). As a result, this radionuclide has the potential to overcome the abovementioned limitations of 68Ga, while offering superior properties. Scandium is known to form complexes with very high stability constants with DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), a widely-used chelator for radiometals in radiopharmaceutical chemistry. The stability constants are comparable to lutetium or yttrium as they all form complexes with square-antiprismatic geometry, whereas they are lower for gallium with distorted octahedron geometry. .sup.68Ga can, therefore, easily be exchanged with .sup.43Sc in radiopharmaceuticals employing the DOTA chelator and can be introduced directly into a GMP-compliant cassette labeling system, such as one provided by Eckert & Ziegler for the labeling of DOTA-ligands in the form of DOTA-TATE, DOTA-TOC, DOTA-BASS, DOTA-PSMA, DOTA-Folate etc.

[0039] The present invention also describes a variety of methods for the production of .sup.43Sc, in sufficient quantities and high radionuclidic purity, by means of a biomedical cyclotron, i.e. with proton beams in the energy range of 10-24 MeV (or deuteron beams in the energy range of 3 to 12 MeV).

[0040] The present invention also describes the required radiochemical procedures to extract 43Sc from its target material in quality and quantity suitable for direct labeling reactions and for future medical application. In addition, procedures to recover the valuable, enriched target materials are disclosed.

Current Status of Research in the Field

[0041] Radiopharmaceuticals comprising metallic radionuclides are gaining in importance in diagnostic and therapeutic nuclear medicine. A prime example is 99mTc, which is currently the most widespread metallic diagnostic radionuclide in nuclear medicine and recently gained attention due to a worldwide supply crisis. The search for alternative procedures is of utmost importance. Examples of therapeutic metallic radionuclides are 90Y used in Zevalin (Ibritumomab tiuxetan labeled with 90Y), 177Lu in Lutathera also known as 177Lu-DOTA-TATE (177Lu-DOTAO-Tyr3-Octreotate; 177Lu-DOTA-DPhe-c(Cys-Tyr-DTrp-Lys-Thr-Cys)-Thr; DOTA: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid), or even 223Ra (223RaCl2) in Xofigo for the treatment of patients with prostate cancer and bone metastases.

[0042] In recent years, somatostatin-receptor-targeted radionuclide therapy of neuroendocrine tumors (NET) has gained much attention. Therapies using 90Y and 177Lu have proven so successful that the International Atomic Energy Agency (IAEA), in cooperation with EANM and SNMMI, has recently issued a practical guidance on peptide receptor radionuclide therapy (PRRNT) for NET. PRRNT was first administered in 1996 in Basel, Switzerland. Other therapies targeting G-protein coupled receptors with peptides, the folate receptor or using monoclonal antibodies conjugated to suitable metallic radionuclides are currently in pre-clinical and clinical trials or are already licensed as radiopharmaceuticals. Quite often, these pharmaceuticals can also be labeled with a relatively short-lived diagnostic radionuclide, especially if the pharmacokinetics is fast. Central to research efforts are isotopes of elements that offer ideal radionuclidic pairs for diagnostic and therapeutic purposes (theranostics or theragnostics). In this way, the same pharmaceutical entity could be labeled with either a diagnostic or a therapeutic nuclide and, due to negligible isotopic effects, one can assume that the therapeutic effect will take place in the positions previously identified by imaging. There is hope that such an approach will facilitate the correct therapy planning and dosimetry of patients, a problem which has not effectively been solved to date.

[0043] An inspection of the chart of nuclides reveals that very few such matched pairs exist, especially if one requirement is that the diagnostic radionuclide must be suitable for PET. No suitable matched positron emitter exists for the two most widely-employed therapeutic radio-nuclides in PRRNT, 90Y and 177Lu (86Y with a low positron branch of 31.9% and numerous high-intensity, high-energy gamma-rays cannot be considered as particularly suitable without the application of correction methods and also concerning radiation dose to patients and personnel, but has been used in patients nonetheless).

[0044] Therefore, radionuclides that behave similarly chemically, resulting in comparable biological behavior, should be taken into consideration. Recently, the diagnosis of NET was successfully performed using 68Ga-radiolabeled derivatives of octreotide. 68Ga is obtained from a 68Ge/68Ga radionuclide generator system and has a half-life of 1.13 h. While diagnostic results are far superior to Single-Photon Emission Computed Tomography (SPECT) of 111 In-radiolabeled derivatives, there are drawbacks to using 68Ga. The relatively short half-life requires each site operating a PET scanner to also set up a radiopharmaceutical production site, fulfilling all new requirements imposed by legislation related to GMP. Furthermore, current 68Ge/68Ga radionuclide generator systems are limited to about 2 GBq of activity, which results in the production of not more than two to three patient doses per generator elution. The half-life of 68Ge (270.82 d) requires an annual replacement of the generator, at best. The current system makes 68Ga-labeled radiopharmaceuticals and its required infrastructure labor-intensive and, thus, is seen as an expensive application, as experienced by the applicants' recent introduction of 68Ga-DOTA-TATE.

[0045] Compared to e.g. .sup.18F-labeled compounds that can be synthesized in GMP-certified radiopharmacies and delivered to hospitals operating PET centers over further distances, the abovementioned drawbacks of 68Ga may limit the widespread application of this radionuclide for PET imaging. Furthermore, it has been shown that 68Ga-labeled somatostatin analogues show different affinity profiles for human somatostatin receptor subtypes SST1-SST5, compared to their 177Lu and 90Y counterparts used for therapy. As a result, a correct therapy planning and dosimetry of patients based on 68Ga imaging appears questionable.

[0046] Taking the abovementioned statements into account, 44Sc-radiolabeled radiopharmaceuticals were considered as an alternative, especially since the chemical behavior of Sc is expected to be more similar to Y and Lu than its Ga counterpart. This radionuclide, with an attractive half-life of 3.92 h, can be obtained from a 44Ti/44Sc radionuclide generator system, or be produced at a 10-20 MeV biomedical cyclotron via the 44Ca(p,n)44Sc nuclear reaction, producing a much greater yield than extracting it from a generator.

[0047] The only serious drawback of 44Sc as positron-emitting radionuclide is the co-emission of an 1157 keV gamma-ray with 99.9% intensity. Compton scattered gamma-rays can interfere with the correct reconstruction of the location of the annihilation reaction of the positron and, thus, impair the obtained PET image. The high-energy gamma-ray also adds to the radiation exposure of patients and personnel. Nevertheless, it should be mentioned that the co-emitted 1157 keV gamma-ray of 44Sc was used for 3 imaging using detection of + coincidences with liquid xenon as detection medium. The first human patient was diagnosed by administrating 37 MBq of 44Sc-DOTA-TOC (44Sc-DOTAO-Tyr3-octreotide; 44Sc-DOTA-DPhe-c(Cys-Tyr-DTrp-Lys-Thr-Cys)-Thra(ol)). High-quality PET/CT images were recorded even 18 h post injection (p.i.), demonstrating that the uptake kinetics can be followed over a relatively long period compared to the 68Ga-labeled analogue and that an individual dosimetry of a subsequent therapeutic application with a longer-lived 90Y- or 177Lu-analogue may be possible.

[0048] The biomedical cyclotrons used mainly for .sup.18F production are designed to accelerate protons and, quite often, also deuterons. According to the present invention, three nuclear reactions using a biomedical cyclotron are used to produce clinically-relevant activities of 43Sc. The reactions proposed are:

[0049] a) 43Ca(p,n)43Sc, using commercially available, enriched 43Ca (natural abundance 0.153%) at proton beam energies of 5 to 24 MeV;

[0050] b) 42Ca(d,n)43Sc, using commercially available, enriched 42Ca (natural abundance 0.647%) and deuteron beam energies of 3 to 12 MeV, or

[0051] c) 46Ti(p,)43Sc, using commercially available, enriched 46Ti (natural abundance 8.25%) and proton beam energies of 10-24 MeV.

[0052] Due to the relatively low beam energies, the production of 43Sc can be established at most biomedical cyclotrons equipped with a solid target station, resulting in an overall cost reduction due to centralized production. Due to its longer half-life, 43Sc-radiopharmaceuticals can be produced concurrently or ahead of .sup.18F-labeled ones and shipped together to the customer.

[0053] The present disclosure describes the 43Sc production using different production routes and establishes the most appropriate one such that the product can be used for the labeling of compounds for clinical evaluation. Different 43Sc-labeled DOTA-peptides, based on ligands binding mainly to SSTR2, are compared to the 177Lu, 90Y, and 68Ga-labeled counterparts with respect to binding affinity, internalization, stability and in vivo properties.

[0054] 43Sc can be produced at a biomedical cyclotron using three different production routes, which will be discussed in more detail. Its production using an -particle beam in the reaction 40Ca(,n)43Ti.fwdarw..sup.+.fwdarw.43Sc is an option, however, accelerators which are able to deliver -particle beams are scarce and more expensive to operate. Furthermore, the active target thickness is much more limited with -particle beams significantly reducing the overall production yield.

[0055] As a result, the 43Ca(p,n)43Sc, 42Ca(d,n)43Sc, or 46Ti(p,)43Sc reactions are considered. The TENDL-2013 calculations, a TALYS-based evaluated nuclear data library, were used to estimate the activity and the radionuclidic purity that could be obtained by irradiation of commercially-available enriched target materials. Where available, the predicted TENDL-2013 calculations were compared with experimentally-determined production reaction cross sections. It was assumed that 10 mg/cm2 of the enriched target element were irradiated at a beam energy corresponding to the maximum of the predicted excitation function over two hours and an intensity of 25 A. After the irradiation, an one-hour waiting period is considered before chemical processing and a processing time of one hour including the labeling of a pharmaceutical. Assuming an 85% chemical yield of the Sc/Ca separation and an 85% yield of the labeling procedure, the theoretical product yields listed in Table 1 can be expected under the aforementioned conditions. These yields were based on the following isotopic compositions of commercially available, enriched target materials:

[0056] 43Ca-target:

[0057] 40Ca (28.50%), 42Ca (1.05%), 43Ca (57.9%), 44Ca (12.36%), 46Ca (<0.003%), 48Ca (0.19%)

[0058] 42Ca-target:

[0059] 40Ca (17.79%), 42Ca (80.80%), 43Ca (0.39%), 44Ca (0.97%), 46Ca (<0.01%), 48Ca (<0.05%)

[0060] 46Ti-target:

[0061] 46Ti (96.9%), 47Ti (0.45%), 48Ti (2.32%), 49Ti (0.17%),50Ti (0.16%)

TABLE-US-00001 TABLE 1 Calculated yields and radionuclidic purity of three different reactions to produce 43Sc radionuclidic Beam purity energy (% Sc activity) Price1) on 43Sc 44gSc 44mSc 46gSc 47Sc 48Sc 49Sc 43Sc Nuclear CHF/ target 3.89 h 3.97 h 2.44 d 83.79 d 3.35 d 1.82 d 57.2 m 43Sc + 44gSc reaction dose (MeV) (Bq) (Bq) (Bq) (Bq) (Bq) (Bq) (Bq) (%) (%) 43Ca(p, n)43Sc 19.90 9 1.9 109 5.9 108 2.9 106 <3.9 102 1.0 104 2.0 105 >76.26 >99.87 42Ca(d, n)43Sc 10.80 5 2.0 109 1.0 107 3.0 105 <6.9 101 <4.3 104 <2.1 105 <1.3 106 >99.40 >99.91 46Ti(p, )43Sc 24.80 16 2.2 108 2.3 106 5.4 104 7.9 102 1.4 104 98.97 99.97 1)Price of the enriched target material for 1 patient dose (200 MBq), assuming a target recovery yield of 80%.

[0062] The 43Ca(p,n)43Sc nuclear reaction:

[0063] The calculated maximum of the excitation reaction corresponds to about 388 mb (10-27 cm2) at a beam energy of 9 MeV. The calculated cross sections are in reasonable agreement with experimental data and the applicants' own measurements. As can be seen from Table 1, the yield of 2 GBq 43Sc is good, however, co-production of 44gSc is significant. Considering the fact that 44gSc has an almost identical half-life and was discussed as a suitable PET nuclide, all other Sc nuclides contribute <0.12% of the total Sc activity, with the long-lived 46gSc comprising only <2.110-5% of the total activity.

[0064] The 42Ca(d,n)43Sc Nuclear Reaction:

[0065] The calculated maximum of the excitation reaction corresponds to about 280 mb (10-27 cm2) at a beam energy of 5 MeV. The yield of 2 GBq of 43Sc is good and the co-production of 44gSc is <1%. In relation to 43Sc+44gSc, all other Sc radionuclides contribute <0.11% of the total Sc activity, the largest contributor being 49Sc with a half-life of only 57.2 m. The long-lived 46gSc comprises only <3.510-6% of the total activity. In maximum production cross sections of only about 80 mb (10-27 cm2) have been reported. Own measurements indicate production cross sections in the range of 125 to 225 mb (10-27 cm2) for beam energies between 3.6 and 7.8 MeV.

[0066] The 46Ti(p,)43Sc Nuclear Reaction:

[0067] The calculated maximum of the excitation reaction corresponds to about 31 mb (10-27 cm2) at a beam energy of 16 MeV. The available experimental reaction cross section data is about 40 mb at 16 MeV (renormalized to 100% 46Ti isotopic abundance) and, thus, in reasonable agreement. The yield of 0.2 GBq of 43Sc is lower by one order of magnitude compared to the other two production reactions but the co-production of 44gSc is <1%. In relation to 43Sc +44gSc, all other Sc radionuclides contribute <0.02% of the total Sc activity. The long-lived 46gSc comprises only 3.610-4% of the total activity.

[0068] A chemical procedure was established for all three nuclear reactions that quantitatively recovers the enriched target materials. Assuming a conservative recovery yield of 80%, the material costs per patient dose (200 MBq .sup.43Sc) are given in Table 1. The current cost of the target materials is as follows: 43Ca 94.50 CHF/mg, 42Ca 54.00 CHF/mg, and 46Ti 13.65 CHF/mg. For comparison, the cost of 68Ga was calculated at 85 CHF/dose, assuming that a generator can be eluted 200 times before breakthrough of 68Ge starts to occur. The abovementioned considerations are provided to demonstrate that the production costs of 43Sc are insignificant compared to the costs of the radiopharmaceutical product, especially taking into account that biomedical cyclotrons are usually only in operation for few hours per day to produce .sup.18F.

[0069] Taking the yield of 43Sc and the co-production of 46gSc as long-lived contaminant into consideration, the 42Ca(d,n)43Sc reaction appears, currently, to be most favorable. The 46Ti(p,)43Sc reaction also delivers a relatively pure product. For this reason, a careful experimental assessment of the cross section was necessary. The 43Ca(p,n)43Sc reaction remains viable, especially if more highly-enriched 43Ca becomes available. It is, therefore, essential to investigate the product spectrum of all three reactions experimentally and to optimize the production of 43Sc in relation to the long-lived 46gSc by optimization of the beam energy.

[0070] Targets are prepared by pressing either enriched 42Ca or 43Ca in the form of the metal or in the form of Ca compounds such as CaCO3, Ca(NO3)2, CaF2 or CaO powders or Ca metal into the groove of the target holder. The target holder provides a volume of up to 0.28 cm3 accommodating up to 100 mg of the enriched isotope in question. In the case of Ti targets, the enriched material can only be purchased in the form of TiO2. The rapid dissolution of TiO2 in a hot-cell environment presents serious difficulties, if hot sulfuric acid or concentrated HF were to be avoided. As a result, the enriched Ti target material is first quantitatively reduced to Ti metal. As can be seen from Table 1, the use of about 100 mg enriched 46Ti will result in the production of >10 patient doses per irradiation, thus, making the 46Ti(p,) reaction a viable option, despite the low production cross section.

[0071] A chemical strategy to isolate 43Sc from irradiated target materials in quantity and quality sufficient for radiopharmaceutical applications is provided, including the recovery of the valuable target material in question. The product must be in a chemical form that is directly usable for a subsequent labeling process.

[0072] The chemical strategy for the production of 43Sc from enriched Ca target material will be similar to the one established for 44Sc.

[0073] Design, manufacturing and irradiation of enriched .sup.42CaCO.sub.3 or .sup.43CaCO.sub.3 targets:

[0074] To manufacture the targets, 101 mg enriched .sup.42CaCO.sub.3 or .sup.43CaCO.sub.3 powder is placed on top of 160 mg graphite powder (99.9999%) and pressed with 10 t of pressure. The targets have dimensions of 0.4-0.5 mm thickness and a diameter of 16 mm (the pressed .sup.42CaCO.sub.3 or .sup.43CaCO.sub.3 powder have a calculated depth of 190 m and diameter of 6 mm in the center of the disc). The encapsulated .sup.42CaCO.sub.3 or .sup.43CaCO.sub.3 pressed target is placed in a target holder system before introduction into the irradiation facility (see FIG. 1). The thickness of the target is driven by the high cost of the enriched material and, therefore, can be increased for production runs.

[0075] FIG. 1 indicates a possible target design showing the position and relative thickness of the target material after pressing together with the graphite powder. The target material is covered by an aluminum lid in the bombardment configuration.

Preparation of Resin Columns:

[0076] A column (1 mL cartridge fitted with 20 m frit, cut to a length of 27 mm) is filled with 70 mg of DGA resin (Triskem International, France) and a 20 m frit placed on top of the resin. The DGA column is preconditioned with 3 M HCl. A second column is used to concentrate the .sup.43Sc. Two methods can be followed for the concentration of product. Method A: The second column (1 mL cartridge fitted with 20 m frit) was filled with 140 L of DOWEX 50W-X2 and a 20 m frit placed on top of the resin. The column is preconditioned with 0.1 M HCl solution. Method B: Alternatively, SCX (Agilent Technologies Inc., USA) cartridges are used for the concentration step, which can be used as purchased without preconditioning.

[0077] Separation of .sup.43Sc from Calcium Target Material:

[0078] The activated target is removed from its aluminum encapsulation and transferred into a glass vial (reaction vessel), dissolved in 2.5 mL 3 M HCl and loaded onto the DGA column, being passed over a 10 mm long filter (1 mL cartridge fitted with a 20 m frit) beforehand. The target container is rinsed with 2.5 mL 3 M HCl and the solution passed over the DGA resin. A further 4 mL 3 M HCl is applied directly onto the DGA column to ensure complete removal of residual Ca(II). A system of syringes and three-way valves are used to transfer solutions from outside into the hot cell (FIG. 2). The first column is directly connected to the second column and the .sup.43Sc eluted from the DGA resin with 4 mL 0.1 M HCl. The solution is sorbed on the second column containing either DOWEX 50W-X2 (Method A) or SCX (Method B) cation exchange resin. The elution of .sup.43Sc is performed via a separate valve (FIG. 2) using 1.5 mL 0.75 M NH.sub.4-acetate/0.2 M HCl (pH 4.5-5.0) for Method A and 0.7 mL 5 M NaCl/0.13 M HCl (pH 0-0.5) for Method B, respectively. In order to collect .sup.43Sc in a suitably small volume the acetate/HCl eluate (Method A) is fractionized into three Eppendorf vials, each containing 500 L. The activity of the eluted fractions is monitored with a radioactivity sensor. Fractionized collection is not necessary in the case of Method B. The chemical yield of Sc is >98%.

[0079] FIG. 2 shows a schematic diagram of the .sup.43Sc production panel (Method B) using enriched Ca.

[0080] Enriched .sup.42CaCO.sub.3 or .sup.43CaCO.sub.3 Target Material Recycling:

[0081] The effluent from the DGA column of several production runs, containing the valuable enriched Ca isotope in question, is evaporated to dryness. The resultant white residue is dissolved in 20 mL deionized water and adjusted to a pH of 4.5-5 with 2.5% ammonia solution and 1 M HCl, respectively. Ca(II) is precipitated as Ca-oxalate by adding 20 mL 0.3 M ammonium oxalate solution. The mixture is left to stand for 2 hours to ensure complete precipitation, filtered through a porcelain filter crucible (8 m pore size) and the oxalate transferred to the carbonate by slowly heating to 500 C. Thus, the valuable enriched materials are again available to manufacture targets. A preceding ICP-OES analysis indicated a Ca concentration of 450 ppm, with minor metallic contaminants (2 ppm Al and 1 ppm Sr). An overall recovery yield of 98% was obtained with the ammonium oxalate precipitation method. The recovered target material provided .sup.43Sc of the same quality as was obtained with targets from the originally-purchased .sup.43CaCO.sub.3.

[0082] The production of 43Sc using the 46Ti(p,)43Sc reaction requires a separation of Sc from Ti and a recycling step for the enriched 46Ti target material. The chemical separation strategy is based on literature data and ongoing research and development at PSI. With the development of a 44Ti/44gSc generator system, the chemical separation of Ti and Sc has already been the subject of some research efforts.

[0083] The chemical separation of Ti and Sc has proven to be difficult, as Ti is easily oxidized and its oxide is only effectively dissolved using hot, concentrated sulfuric acid. A further headache is the fact that extensive heat is required to evaporate the sulfuric acid, as it boils at over 300 C. More recent attempts at separating these two elements involved the use of hydrofluoric acid (HF). HF was used to dissolve the target material, before it was diluted and loaded on an anion exchange resin column. With Ti retained, the eluted Sc (dilute HF and dilute nitric acid) is loaded on to a cation exchange resin and eluted with dilute ammonium acetate. Another system, which involved the separation of 44Ti from Sc target material, saw a concentrated solution of hydrochloric acid being used to pass through an anion exchange resin, allowing the Ti to be retained and the Sc to pass though.

[0084] A chemical strategy to isolate 43Sc produced in the 46Ti(p,) reaction from irradiated Ti target materials in quantity and quality sufficient for radiopharmaceutical applications is provided, including the recovery of the valuable target material in question. The product must be in a chemical form directly usable for a subsequent labeling process.

[0085] Reduction of .sup.46TiO.sub.2:

[0086] Up to 250 mg .sup.46TiO.sub.2 are mixed with 40% surplus CaH.sub.2, metals basis in an oxygen-free Ar-environment. A tablet is pressed with 5t pressure for 2 minutes and in a molybdenum crucible inserted into an Ar-flooded oven. The oven is heated up to 900 C. in about 30 minutes, and the temperature is kept at 900 C. for 1 hour. The oven is cooled down to 100 C., which takes about 2-3 hours. The reduction is complete when the white TiO.sub.2 transformed into black Ti. The tablet is placed on a Millipore-Filter (0.45 m) in a Bchner funnel and washed with about 20 ml deionized water, whereby the tablet disintegrates. The CaO is dissolved by washing with 100-150 mL acetic acid, suprapur (1:4) over a time period of 3 hours. The filter is rinsed with deionized water until the effluent of the Bchner funnel is pH neutral. The resulting Ti-powder is dried in a desiccator overnight.

[0087] Design, Manufacturing and Irradiation of Enriched .sup.46Ti Metal Targets:

[0088] The manufacturing of .sup.46Ti metal targets proceeds analogous to the preparation of enriched CaCO.sub.3-targets. To manufacture the targets, 101 mg enriched .sup.46Ti metal powder is placed on top of 160 mg graphite powder (99.9999%) and pressed with 10 t of pressure. The resulting tablet is encapsulated in aluminum and placed in a target holder system.

[0089] Preparation of Resin Columns:

[0090] A column (1 mL cartridge fitted with 20 m frit, cut to a length of 27 mm) is filled with 70 mg of DGA resin (TrisKem International, France) and a 20 m frit placed on top of the resin. The DGA column is cleaned and preconditioned with 4 mL 6 M HCl and 9 mL 4 M HCl.

[0091] Separation of .sup.43Sc from Titanium Target Material:

[0092] The irradiated .sup.46Ti-graphite target is dissolved in 5 mL 6 M HCl at 180 C. for 10 minutes, 2 mL deionized water is added to dilute the solution to 4 M HCl.

[0093] The starting solution is passed through the DGA resin column. The vial is flushed with 3 mL 4 M HCl, passed through the resin column, with any remaining impurities removed from the DGA column with an additional 8 mL 4M HCl. The DGA column is directly connected to a second column containing SCX cation exchange resin. .sup.43Sc is eluted from the DGA column with 10 mL 0.05 M HCl and sorbed on the SCX column. Elution of the product from the SCX column with 700 L SCX-Eluent (4.8M NaCl/0.1 M HCl) yields .sup.43Sc directly available for labeling reactions. The chemical yield of Sc is >98%.

[0094] Labeling Reactions:

[0095] The product is placed into a Reactivial containing 2 mL 2M sodium acetate buffer and 10 g peptide (DOTA-chelator). The resultant solution is heated at 100 C. for 10 minutes, after which it is passed through a Sep-Pak C18 Lite cartridge (Waters Corporation, USA). The cartridge is rinsed with 2 mL 0.9% saline, before the product is eluted with 2 mL 50% ethanol. The addition of gentisic acid ensures that no radiolysis of the labeled product occurs.

[0096] The applicants believe that 43Sc represents a highly promising radionuclide with unique and important scientific, clinical and industrial implications.