Macrocyclic complexes of scandium radionuclides as precursors for diagnostic and therapeutic radiopharmaceuticals

Majkowska-Pilip, Agnieszka; Bilewicz, Aleksander

doi:10.1016/j.jinorgbio.2010.11.003

Cited by 113 publications

(109 citation statements)

References 42 publications

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“…This allows the formation of stable 44 Sc complexes with DOTA chelators. Recently, it was shown that DOTA was the most preferred chelator for 44 Sc(III) from a series of macrocyclic ligands (33). All 4 amine and carboxyl groups of a DOTA chelator contribute to the complexation of 44 Sc(III), resulting in a stability constant comparable to those of Y(III) and lanthanides (33).…”

Section: Discussionmentioning

confidence: 99%

Promises of Cyclotron-Produced ⁴⁴Sc as a Diagnostic Match for Trivalent β⁻-Emitters: In Vitro and In Vivo Study of a ⁴⁴Sc-DOTA-Folate Conjugate

et al. 2013

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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 5 3.97 h, average b 1 energy [Eb 1 av ] 5 632 keV) as a valuable alternative to 68 Ga (half-life 5 68 min, Eb 1 av 5 830 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 cyclotronproduced 44 Sc and its in vitro and in vivo comparison with the 177 Lulabeled pendant. Methods: 44 Sc was produced via the 44 Ca(p,n) 44 Sc nuclear reaction at a cyclotron (17.6 6 1.8 MeV, 50 mA, 30 min) using an enriched 44 Ca target (10 mg 44 CaCO 3 , 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 mL 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 highyield 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 Luradionuclide tumor therapy. In the past decade, applications of radiometal-based PET have rapidly increased, particularly for oncologic imaging purposes (1). Clinical implementation of 68 Ga-labeled somatostatin analogs (e.g., 68 Ga-DOTATATE, 68 Ga-DOTATOC) for imaging of neuroendocrine tumors has raised attention because of the excellent imaging quality that can be achieved and the on-site availability of 68 Ga (half-life [T 1/2 ] 5 68 min, average b 1 energy [Eb 1 av ] 5 830 keV, intensity 5 89%) by the 68 Ge/ 68 Ga generator (2-6). Somatostatin receptor-targeted PET is currently used for dosimetry before application of 177 Lu-based radionuclide therapy (7). These facts have established the basis of a new era of PET applicat...

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Section: Discussionmentioning

confidence: 99%

Promises of Cyclotron-Produced ⁴⁴Sc as a Diagnostic Match for Trivalent β⁻-Emitters: In Vitro and In Vivo Study of a ⁴⁴Sc-DOTA-Folate Conjugate

et al. 2013

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“…Stability constants of only several scandium(III) complexes with polyaminopolyacetate ligands have been published: EDTA (log K ScL 25.0, [28] 23.9 [40] ), DTPA (log K ScL 22.5, [18] 24.5, [40] 26.3 [29] ), and DOTA (log K ScL 22.5 [18] or 27.0 [20] ). Mostly, the values were determined by non-conventional methods and, thus, those for Sc 3 + -DTPA and Sc 3 + -DOTA systems were re-examined here by potentiometry, which is the most common method for stability constant determinations.…”

Section: Stability Constants Of the Scandium(iii) Complexesmentioning

confidence: 99%

“…[18,20] Stability constants of scandium(III) complexes with these ligands are much higher (4-6 orders of magnitude) than those of lanthanide(III) or gallium(III) complexes. [33,42,43] It is expected, as interaction of such a small hard metal ion with highly charged polycarboxylate ligands is stronger (in comparison with Ln 3 + -complexes, eight donor atoms) and the Sc 3 + ion employs all available donor atoms of the ligands (in comparison with Ga 3 + complexes with six donor atoms).…”

Section: Stability Constants Of the Scandium(iii) Complexesmentioning

confidence: 99%

“…It has been shown that DOTA derivatives are suitable ligands for scandium radioisotopes. [18][19] Their oligopeptide, [8,11,[20][21][22] antibody, [23] or other [24,25] conjugates have been investigated for complexation of the scandium radionuclides. Surprisingly, only several studies dealing with structure of DTPA or DOTA scandium(III) complexes have been published.…”

Section: Introductionmentioning

confidence: 99%

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Thermodynamic and Kinetic Study of Scandium(III) Complexes of DTPA and DOTA: A Step Toward Scandium Radiopharmaceuticals

Pniok

Kubíček

Havlíčková

et al. 2014

Chemistry A European J

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Diethylenetriamine-N,N,N',N'',N''-pentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) scandium(III) complexes were investigated in the solution and solid state. Three (45)Sc NMR spectroscopic references suitable for aqueous solutions were suggested: 0.1 M Sc(ClO4)3 in 1 M aq. HClO4 (δSc =0.0 ppm), 0.1 M ScCl3 in 1 M aq. HCl (δSc =1.75 ppm) and 0.01 M [Sc(ox)4](5-) (ox(2-) = oxalato) in 1 M aq. K2C2O4 (δSc =8.31 ppm). In solution, [Sc(dtpa)](2-) complex (δSc = 83 ppm, Δν = 770 Hz) has a rather symmetric ligand field unlike highly unsymmetrical donor atom arrangement in [Sc(dota)](-) anion (δSc = 100 ppm, Δν = 4300 Hz). The solid-state structure of K8[Sc2(ox)7]⋅13 H2O contains two [Sc(ox)3](3-) units bridged by twice "side-on" coordinated oxalate anion with Sc(3+) ion in a dodecahedral O8 arrangement. Structures of [Sc(dtpa)](2-) and [Sc(dota)](-) in [(Hguanidine)]2[Sc(dtpa)]⋅3 H2O and K[Sc(dota)][H6 dota]Cl2⋅4 H2O, respectively, are analogous to those of trivalent lanthanide complexes with the same ligands. The [Sc(dota)](-) unit exhibits twisted square-antiprismatic arrangement without an axial ligand (TSA' isomer) and [Sc(dota)](-) and (H6 dota)(2+) units are bridged by a K(+) cation. A surprisingly high value of the last DOTA dissociation constant (pKa =12.9) was determined by potentiometry and confirmed by using NMR spectroscopy. Stability constants of scandium(III) complexes (log KScL 27.43 and 30.79 for DTPA and DOTA, respectively) were determined from potentiometric and (45)Sc NMR spectroscopic data. Both complexes are fully formed even below pH 2. Complexation of DOTA with the Sc(3+) ion is much faster than with trivalent lanthanides. Proton-assisted decomplexation of the [Sc(dota)](-) complex (τ1/2 =45 h; 1 M aq. HCl, 25 °C) is much slower than that for [Ln(dota)](-) complexes. Therefore, DOTA and its derivatives seem to be very suitable ligands for scandium radioisotopes.

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“…Folic acid binds selectively to the folate receptor (FR), which is expressed on a variety of tumor types, including cancer of the ovaries and of the lungs (15,16). The DOTA-chelator can be used for stable coordination of Sc as previously demonstrated (13,17). Finally, there is a small-molecular-weight albuminbinding entity (18) integrated in the folate conjugate cm10.…”

mentioning

confidence: 99%

Promising Prospects for ⁴⁴Sc-/⁴⁷Sc-Based Theragnostics: Application of ⁴⁷Sc for Radionuclide Tumor Therapy in Mice

et al. 2014

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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! b − 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 Sccm10 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.

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Macrocyclic complexes of scandium radionuclides as precursors for diagnostic and therapeutic radiopharmaceuticals

Cited by 113 publications

References 42 publications

Promises of Cyclotron-Produced ⁴⁴Sc as a Diagnostic Match for Trivalent β⁻-Emitters: In Vitro and In Vivo Study of a ⁴⁴Sc-DOTA-Folate Conjugate

Promises of Cyclotron-Produced ⁴⁴Sc as a Diagnostic Match for Trivalent β⁻-Emitters: In Vitro and In Vivo Study of a ⁴⁴Sc-DOTA-Folate Conjugate

Thermodynamic and Kinetic Study of Scandium(III) Complexes of DTPA and DOTA: A Step Toward Scandium Radiopharmaceuticals

Promising Prospects for ⁴⁴Sc-/⁴⁷Sc-Based Theragnostics: Application of ⁴⁷Sc for Radionuclide Tumor Therapy in Mice

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Macrocyclic complexes of scandium radionuclides as precursors for diagnostic and therapeutic radiopharmaceuticals

Cited by 113 publications

References 42 publications

Promises of Cyclotron-Produced 44Sc as a Diagnostic Match for Trivalent β−-Emitters: In Vitro and In Vivo Study of a 44Sc-DOTA-Folate Conjugate

Promises of Cyclotron-Produced 44Sc as a Diagnostic Match for Trivalent β−-Emitters: In Vitro and In Vivo Study of a 44Sc-DOTA-Folate Conjugate

Thermodynamic and Kinetic Study of Scandium(III) Complexes of DTPA and DOTA: A Step Toward Scandium Radiopharmaceuticals

Promising Prospects for 44Sc-/47Sc-Based Theragnostics: Application of 47Sc for Radionuclide Tumor Therapy in Mice

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Promises of Cyclotron-Produced ⁴⁴Sc as a Diagnostic Match for Trivalent β⁻-Emitters: In Vitro and In Vivo Study of a ⁴⁴Sc-DOTA-Folate Conjugate

Promises of Cyclotron-Produced ⁴⁴Sc as a Diagnostic Match for Trivalent β⁻-Emitters: In Vitro and In Vivo Study of a ⁴⁴Sc-DOTA-Folate Conjugate

Promising Prospects for ⁴⁴Sc-/⁴⁷Sc-Based Theragnostics: Application of ⁴⁷Sc for Radionuclide Tumor Therapy in Mice