Coordination chemistry: ligands selected for the complexation of Scandium 71

Scandium chemistry has not been explored like any other transition elements The use of scandium in both inorganic and organometallic chemistry has been of growing interest, proof is the number of compounds synthesized and characterized by X-ray diffraction or other methods. There is a large number of available ligands complexing scandium but many of those are for metallurgical applications [68] or for systems of environmental remediation.

However, the literature on complexation of scandium has very few applications in biological environments [69,70,71,72].

In the design of radiopharmaceuticals complexes, the first factor considered is the thermodynamic constant. Certainly it does not necessarily indicate that the complex has exactly the same behavior in vivo, but it is often used as the primary selection criterion for the development of pharmaceuticals. It is quantified by the measurement of metal-ligand complexation constant K_ML. However, knowledge of the stability of various metal complexes is not sufficient for comparing the affinity of ligands since they can exhibit different acid-base properties and denticity. It is then preferable to determine the concentration of free metal not complexed by calculation methods of speciation. This concentration is expressed as the logarithm of p[M] and used to quantitatively compare the ability of various ligands to

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complex metal. A complex with a low constant will tend to cause transchelation by other systems (biomolecules competitors).

The kinetic inertness of the complexes towards the demetallation is the second parameter that must be studied. The important thing here is to determine if the complex is susceptible to dissociate within time since injected in vivo. More the complex is stable kinetically more decomplexation is avoided in the presence of metal ions competitors (transmetallation).

Generally, the kinetics of decomplexation is observed in highly acidic media due to the exchange with protons.

The macrocyclic ligands can bind various metal ions, particularly trivalent lanthanide to form monomers complexes which are soluble in water. Due to the cyclic and organized nature of the ligands, the complexes formed are thermodynamically stable and kinetically inert. This class of compounds has been investigated for medical applications, e.g. as contrast agents in magnetic resonance imaging (MRI) [73,74,75,76,77,78] or as bifunctional chelating agents (BFCA) for labeling biomolecules specific for molecular imaging and / or targeted radiotherapy [79,80,81]. Among the chelators proposed, the polyaminocarboxylic acids linear and macrocyclic derivatives respectively of H5DTPAand H4DOTA, are of great releance.

The DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelator is commonly used to complex metal ions in solution. The octacoordinated structure using four nitrogen and four carboxyl side chains has been reported for DOTA and its derivatives [82,83]. This degree of coordination is perfectly suitable with scandium.

DOTA and its derivatives have been successfully conjugated to a certain number of somatostatin analogues, and radiopharmaceuticals obtained have good pharmacological parameters [84,85].

DOTA is suitable for chelating ⁶⁷Ga, ⁹⁰Y and ¹¹¹In. It has been shown that ⁹⁰Y-DOTA conjugates have very good in vivo pharmacokinetics properties [86]. However, in these radiopharmaceuticals, the chelating moiety modifies the original peptide conformation, leading to a more difficult binding to its receptor. DOTA and its derivatives are of particular interest for radiolabeling peptides and biomolecules by lanthanides. The macrocycle is pre- organized so it binds the metal with relatively high thermodynamic stability. pKa values for the carboxyl groups of DOTA range between 2 and 5. In addition, the high hydrophilicity of the acetate arm of DOTA promotes blood clearance of unlabeled DOTA-peptide relative to radiopharmaceutical and thus reduces the competition between the two chemical species at the receptor [87].

An important advantage of using analogues of DTPA as bifunctional ligand for indium-111 is their extremely high efficiency of complexation (fast complexation with high radiochemical

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purity) under mild conditions [88,89], but the low stability of these complexes in vivo, results in the dissociation of the radionuclide from its chelate. In the case of use of DTPA with yttrium-90 or lutetium-177, there is a significant risk of irradiation of organs such as bone marrow [90]. As against, analogs of the DOTA chelating Indium-111 have a high stability in vivo, However, the kinetics of the radiolabeling with DOTA is usually slow and requires a relatively high temperature reaction, while the DTPA complex can be formed at room temperature [87]. If small peptides can withstand relatively high temperatures (below 100 °C) the antibodies, at these temperatures, lose much of their immunoreactivity. Although DOTA form metal chelates very stable in solution, slow complexation kinetics remains an important obstacle that limits the routine use of this chelator in radiopharmaceuticals.

Data for complexation of radioisotopes with ligands such as DTPA, DOTA, NOTA and TETA were published long ago [91]. Studies performed recently [24] allowed to determine the complexation constants of scandium (III) with acyclic (figure 5 and table 2) (H4EDTA, H5DTPA) and cyclic ligands (H4DOTA, H4TETA and H3NOTA).

Figure 5: structure of the ligands studied with Sc

The in vitro stability of these ligands was then investigated (serum and bone substitute). Only DOTA was sufficiently stable over several days towards these two biological media to be considered the following steps. In fact, the next step consists in coupling this chelating molecule with proteins and / or antibodies that specifically target tumor cells.

Table 2: Stability constants of studied ligands with Sc determined by the free-ion selective radiotracer extraction method (I = 0.1 M NaClO4, CL= 10^-9 to ^10-3M) [24]

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I.3.3. Radioisotopes of Scandium of interest for nuclear medicine

For its use in medicine a radionuclide should be easily accessible, can be quickly incorporated into the radiopharmaceutical and with a half-life sufficiently long to allow monitoring the physiological process of interest, but short enough to limit internal irradiation of the patient.

The ⁴⁶Sc is a beta emitter radionuclide (the average beta energy 0.3569 MeV) with a half-life of 83.8 days (table 3), it emits two gamma rays (0.889 MeV and 1.120 MeV) [13]. A longer half-life and a high beta emission energy, make the ⁴⁶Sc ideal to the evaluation of the chemical, the stability and biodistribution of the scandium radiolabeled compounds [71].

However, these characteristics of longer half-life and emission are not suitable for clinical studies [92]. ⁴⁶Sc has been used in many biological studies in the literature. For example, a large parathyroid absorption of the ⁴⁶Sc has suggested the use of this radionuclide in the treatment of tumors and diagnostic studies [93].

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Table 3: radioisotopes of Sc of interest in nuclear in medicine

Furthermore, the radiolabelled ⁴⁶Sc has been widely used in the determination of blood flow in many cardiovascular studies [94,95]. Recently, studies of stability and biodistribution of the

46Sc-bleomycin complex were carried out in order to its use as a potential therapeutic complex [92].Two other isotopes of scandium, ⁴⁷Sc and ⁴⁴Sc radionuclides are respectively useful for radiotherapy and imaging. The ⁴⁷Sc radionuclide with a half-life of 3.35 days decays by emitting a radiation β^- with a maximum energy of 600 keV. It also emits at low-energy γ radiation (E = 159 keV) suitable for SPECT imaging. The ⁴⁷Sc radionuclide has already been studied for its potential interest for beta-RIT (radioimmunotherapy) [72,96,97].

Use of ⁴⁷Sc radionuclide, as an alternative to the ¹⁷⁷Lu radionuclide, has been proposed in previous reviews [72,98,99,100]. Another radionuclide of scandium, ⁴⁴Sc (T1/2 = 3.92h) is a β⁺ emitter ideal for PET diagnosis. It decays in 94.27% of cases by emitting a positron [101], accompanied in a picosecond frame by a single γ photon of 1.157 MeV. As shown in the decay scheme of ⁴⁴Sc (figure 6), the life time of the first excited level of ⁴⁴Ca is only 2.61 ps, so that the 1157 keV photon may be considered emitted almost simultaneously with the positron.

44

21Sc ₂₀⁴⁴Ca^∗+ e + v⁺ _e

44

21Sc ₂₀⁴⁴Ca^∗+ e + v⁺ _e

44 ∗ 44

20⁴⁴Ca ^∗ ₂₀⁴⁴Ca+ɣ

20⁴⁴Ca ^∗ ₂₀⁴⁴Ca+ɣ

20Ca ₂₀Ca+ɣ

44Sc ^44mSc ⁴⁷Sc ⁴⁶Sc

Half-life 3.92h 2.44d 3.35d 83.8d

Emitter β⁺ γ 98.8% β^- β^-

Maximum kinetic energy of β (keV)

1474 :94.27% 440.9 :68.4%

600.3 :31.6%

356.9 :100%

Gamma energy (keV) 1157 :99.9% 271 : 98.8% 159.4 :68.4% 889 : 100%

1120 : 100%

Production reaction ⁴⁴Ca (p, n) (d, 2 n)

44Ca (p, n) (d, 2 n)

47Ti (p, n) (d, 2 n)

45Sc (n, γ)

76 Figure 6: Scheme of energy levels of ⁴⁴Sc [12]

44Sc can be used as an alternative to ⁶⁸Ga, since it has a longer half-life and form stable radiolabeled complexes with a similar structure compared to the ⁹⁰Y and ¹⁷⁷Lu, which is important in the planning of radiotherapy [102]. ⁴⁴Sc can be obtained from the generator

44Ti/⁴⁴Sc [103,104,63] or can be produced by nuclear reaction from ⁴⁴Ca in small cyclotrons.

Currently the high energy intensity of the Cyclotron ARRONAX [21] allows the production of ⁴⁴Sc via the nuclear reaction ⁴⁴Ca (d, 2n).

From production via ⁴⁴Ca, the isometric state of ⁴⁴Sc, ^44mSc is co-produced with ⁴⁴Sc. ^44mSc has the same characteristics as ⁴⁴Sc, but with a longer half-life (2.44 days versus 3.92h). Its longer half-life may facilitate dosimetric studies in order to use the innovative ⁴⁷Sc radionuclide for radiotherapy. Indeed, ^44mSc and ⁴⁷Sc have half-lives of the same order (2.44 days versus 3.35 days) to monitor metabolic pathways, which is an advantage compared to the generator ⁴⁴Ti/⁴⁴Sc [24]. Therefore, therapeutic ⁴⁷Sc together with diagnostic ⁴⁴Sc can be used as ‗‗matched pair‘‘ in theranostic approach [97]. Due to these features, ^44mSc/⁴⁴Sc could be considered as a potential in vivo generator for PET imaging and as an alternative to the ⁶⁴Cu /⁶⁷Cu pair.

Finally, ⁴⁴Sc was identified as the best candidate for 3γ PET imaging, based on the location in 3D and event by event of a particular emitter (β⁺ ,γ).

It emits a positron in temporal coincidence with a γ photon as in PET, positron annihilates with an electron to give two γ-rays of 511 keV emitted back to back, and these are then

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detected by a PET camera for example. The direction of the third gamma radiation is reconstructed using a Compton telescope with liquid xenon [5].