An Unusual Pair: Facile Formation and In Vivo Validation of Robust Sc–¹⁸F Ternary Complexes for Molecular Imaging

Abstract

Fluorine-18 remains the most widely clinically utilized radionuclide globally for positron emission tomography (PET). The emergence of therapeutic isotopes for the management of disease has produced a pronounced interest in matched, theranostic isotope pairs that can be employed in tandem for the diagnosis and stratification of patients for subsequent radiotherapy. 18 F, however, does not have a suitable therapeutic isotopologue. Here, we demonstrate that the formation of [ 18 F][ScÀ F] ternary complexes is feasible under mild, aqueous conditions, producing chemically robust radiopharmaceuticals in high radiochemical yield and specific activity. A corresponding in vivo study with a cancer-targeting [ 18 F][ScÀ F] tracer indicates excellent in vivo stability and produces exquisite PET image quality, rendering the 18 F/ 47 Sc isotope pair an unusual, yet chemically matched theranostic pair with excellent potential for clinical translation.

Radiolabeling and in vivo evaluation of lanmodulin with biomedically relevant lanthanide isotopes

“…24 To functionalize LanM with a disease-specific targeting vector, the protein was conjugated to a short, peptide-based targeting vector selective for the prostate specific membrane antigen (PSMA), a well-studied antigen overexpressed on the surface of prostate cancer cells. [32][33][34][35] In addition to the wellestablished nature of the corresponding targeting vector's chemistry, a wealth of in vivo imaging and biodistribution data has been reported on PSMA-targeted constructs; therefore, previously published datasets serve as suitable means to evaluate the relative stability and performance of new PSMAtargeting entities. A maleimide-functionalized version of the small peptide targeting vector used in the clinically approved 177 Lu-PSMA-617 was synthesized with manual solid phase peptide synthesis methods (Fig.…”

Synthesis, Characterization, and Computational Studies on Gallium(III) and Iron(III) Complexes with a Pentadentate Macrocyclic bis-Phosphinate Chelator and Their Investigation As Molecular Scaffolds for 18F Binding

“…The 1 H, 13 C{ 1 H}, and 13 C DEPT-135 NMR spectra (d 4 -MeOH) of the H 2 (Bn-NODP) (and its HCl and Na + salts) are consistent with incorporation of two chemically equivalent phosphinic acid functions into Bn-tacn, leading to three distinct tacn-CH 2 groups in the 13 C{ 1 H} NMR spectra (the two CH 2 groups adjacent to the N atoms bearing the phosphinate pendant arms), with the expected large doublet 1 J PC couplings evident on the CH 2 P and ipso-CP resonances, and smaller, longer-range couplings observed on the o-, m-, and p-CH groups of the phenyl ring directly bonded to P. The 31 P{ 1 H} NMR spectrum of the H 2 (Bn-NODP) shows a singlet at 27.21 ppm, between those of the HCl salt (34.55 ppm) and the Na + salt (24.42 ppm). Similar trends were observed in the data reported for the tris-phosphinic acid derivative of tacn, H 3 (NOTP) (NOTP = 1,4,7-triphenylphosphinate-1,4,7-triazacyclononane).…”

“…With this in mind, radiotracers based upon inorganic-fluoride compounds could offer several important advantages, opening up new chemistries, a single-step approach using a preformed metal chelate scaffold, direct radiofluorination, and simple purification under mild conditions. , Certain main group and transition metal species show high fluoride affinities, which can result in favorable thermodynamics and fast reaction kinetics for binding to radiofluorine; these inorganic scaffolds can then be conjugated via the macrocyclic coligand to a range of peptides. In particular, work from a number of groups has focused on boron and silicon-based molecules bearing fluorine-18 as PET tracers, while trivalent main group metal ions (aluminum­(III), − gallium­(III), − indium­(III)) and transition metal ions (scandium­(III) and iron­(III)) bearing mostly macrocyclic chelators based upon the tacn (1,4,7-triazacyclononane) core have attracted considerable interest as potential metal-chelate scaffolds for radiofluorine. Coordination to macrocyclic ligands increases the thermodynamic and kinetic stability of the complexes, therefore reducing the likelihood of byproduct formation during radiolabeling and reducing the likelihood of hydrolysis and liberation of 18 F – in vivo .…”

“…14 The radiochemical purities (RCPs) of the various formulated solutions over time are shown in Table 5 and graphically Infrared spectra were recorded using a PerkinElmer Spectrum 100 spectrometer in the range 4000−200 cm −1 , with samples prepared as Nujol mulls between CsI plates. 1 H, 13 C{ 1 H}, and 13 C DEPT-135 NMR spectra were recorded using a Bruker AV 400 spectrometer and referenced to the residual protio-resonance of the solvent. 19 F{ 1 H} and 31 P{ 1 H} were recorded in d 4 -MeOH solutions using a Bruker AV 400 spectrometer and referenced to CFCl 3 and external 85% H 3 PO 4 , respectively.…”

“…13 C{ 1 H} NMR (d 4 -MeOH/ppm): δ 139.69 (d, 1 J PC = 123.2 Hz, ipso-C, Ph), 134.31 (ipso-C, Bn), 132.60 (d, 3 J PC = 9.5 Hz, m-CH, Ph), 132.15 (s, m-CH, Bn), 131.82 (d, 4 J PC = 2.9 Hz, p-CH, Ph), 130.34 (s, p-CH, Bn), 130.16 (s, o-CH, Bn), 129.36 (d, 2 J PC = 11.7 Hz, o-CH, Ph), 61.12 (CH 2 Bn), 58.59 (d, 1 J PC = 106.4 Hz, CH 2 P), 55.39, 54.01 (br, 2 × CH 2 , tacn), 52.83 (CH 2 NBn, tacn). 31 P{ 1 H} (d 4 -MeOH): δ 24.41 (s).…”