Preclinical Evaluation of [155/161Tb]Tb-Crown-TATE—A Novel SPECT Imaging Theranostic Agent Targeting Neuroendocrine Tumours

Abstract

Terbium radioisotopes (149Tb, 152Tb, 155Tb, 161Tb) offer a unique class of radionuclides which encompass all four medicinally relevant nuclear decay modalities (α, β+, γ, β−/e−), and show high potential for the development of element-matched theranostic radiopharmaceuticals. The goal of this study was to design, synthesise, and evaluate the suitability of crown-TATE as a new peptide-conjugate for radiolabelling of [155Tb]Tb3+ and [161Tb]Tb3+, and to assess the imaging and pharmacokinetic properties of each radiotracer in tumour-bearing mice. [155Tb]Tb-crown-TATE and [161Tb]Tb-crown-TATE were prepared efficiently under mild conditions, and exhibited excellent stability in human serum (>99.5% RCP over 7 days). Longitudinal SPECT/CT images were acquired for 155Tb- and 161Tb- labelled crown-TATE in male NRG mice bearing AR42J tumours. The radiotracers, [155Tb]Tb-crown-TATE and [161Tb]Tb-crown-TATE, showed high tumour targeting (32.6 and 30.0 %ID/g, respectively) and minimal retention in non-target organs at 2.5 h post-administration. Biodistribution studies confirmed the SPECT/CT results, showing high tumour uptake (38.7 ± 8.0 %ID/g and 38.5 ± 3.5 %ID/g, respectively) and favourable tumour-to-background ratios. Blocking studies further confirmed SSTR2-specific tumour accumulation. Overall, these findings suggest that crown-TATE has great potential for element-matched molecular imaging and radionuclide therapy using 155Tb and 161Tb.

Rearmed Bifunctional Chelating Ligand for 225Ac/155Tb Precision-Guided Theranostic Radiopharmaceuticals─H4noneunpaX

“…1 H NMR (300 MHz, CDCl 3 , 298 K) 7.90 (2H, dd, 3 J = 7.3 Hz, 4 J = 1.1 Hz, 10-CH), 7.80 (2H, dd, 3 J = 8.1 Hz, 4 J = 1. 4 Hz, 8-CH), 7.75 (2H, t, 3 J = 7.5 Hz, 9-CH), 3.94 (4H, s, 7-CH 2 ), 3.90 (6H, s, 11-CH 3 ), 3.49 (2H, t, 3 J = 5.6 Hz, 2-CH 2 ), 3.44 (2H, t, 3 J = 5.8 Hz, 3-CH 2 ), 3.40 (4H, s, 5-CH 2 ), 2.84 (2H, t, 3 J = 5.8 Hz, 4-CH 2 ), 2.74 (2H, t, 3 J = 5. 6 Hz, 1-CH 2 ), 1.35 (18H, s, 6-C(CH 3 ) 3 ).…”

“…Macrocyclic chelating ligands, such as DOTA, Chart , are well-established as versatile platforms for sequestering different metal ions, forming thermodynamically stable and kinetically inert metal complexes; however, this is often at the expense of specificity/selectivity and requires high temperatures for metal ion incorporation . Notably, significant research studies by the groups of Yang et al , and Wilson et al – have discovered macrocyclic ligands with expanded core frameworks (e.g., crown, macropa, macrodipa), which demonstrate more facile complexation characteristics and show interesting size–selectivity relationships. Furthermore, the bispidine class of chelating ligands, which have been extensively explored by Comba et al, have achieved favorable complexation properties with both large and small metal ions under mild conditions. , Nonmacrocyclic chelating ligands, such as EDTA and DTPA, have been extensively investigated over decades for metal ion chelation owing to their fast complexation kinetics under mild conditions, and their widespread application has been found in the medicinal sector in combination with thermally sensitive drug molecules; , however, such chelators can exhibit fast decomplexation kinetics, leading to poor in vivo stability.…”

“…Macrocyclic chelating ligands, such as DOTA, 1 Chart 1, are well-established as versatile platforms for sequestering different metal ions, forming thermodynamically stable and kinetically inert metal complexes; however, this is often at the expense of specificity/selectivity and requires high temperatures for metal ion incorporation. 2 Notably, significant research studies by the groups of Yang et al 3,4 and Wilson et al 5−13 have discovered macrocyclic ligands with expanded core frameworks (e.g., crown, macropa, macrodipa), which demonstrate more facile complexation characteristics and show interesting size−selectivity relationships. Furthermore, the bispidine class of chelating ligands, which have been extensively explored by Comba et al, have achieved favorable complexation properties with both large and small metal ions under mild conditions.…”

“…Given the inherent challenges in the directed synthesis of ligands with symmetric donor substitution and the require-Chart 1. Chemical Structures of Discussed Ligands [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]26,27 ments to often "break" symmetry in the pursuit of bifunctional derivatives for radiopharmaceutical applications, 22 an assessment of the exact impacts of an inverted donor group arrangement on metal ion chelation is warranted. This inverted "syn" constitutional arrangement may give several advantages, particularly in regard to synthesis: protecting group strategies can be circumvented through rational synthetic design, and the incorporation of bifunctional handles within the core framework is synthetically more accessible, allowing for streamlined tuning of the pharmacokinetic profile of new radiopharmaceuticals.…”

“…H NMR (400 MHz, D 2 O, 298 K) 8.03 (1H, s, 14-CH), 7.94−7.83 (2H, m, 8-and 9-CH), 7.62 (1H, dd, 3 J = 6 3. Hz, 4 J = 2.0 Hz, 7-CH), 7.58 (1H, d, 4 J = 2.7 Hz, 12-CH),7.24 (1H, d,4 J = 2.h i b i t e d . = 0).…”