Toward Personalized Medicine: One Chelator for Imaging and Therapy with Lutetium-177 and Actinium-225

Abstract

We report a nonadentate bispidine (3,7-diazabicyclo[3.3.1]nonane) that unveils the potential to bind theranostically relevant radionuclides, including indium-111, lutetium-177, and actinium-225 under mild labeling conditions. This radiopharmaceutical candidate allows the simultaneous application of imaging and treatment (radionuclide theranostics) without changing the type of the bioconjugate; that is, it allows the strong binding to an imaging and a therapeutic radionuclide by the same chelator. Since sophisticated coordination chemistry is required to achieve high thermodynamic and kinetic stability (inertness), it is not surprising that only a few chelators have been reported that are able to strongly bind several radionuclides to a satisfactory extent. Bispidine-derived ligands have proven to be ideal for di- and trivalent metal ions with generally fast complexation kinetics and high in vitro and in vivo stabilities. The presented (radio)complexes are formed under mild conditions (pH 6, <40 °C) and exhibit thermodynamic stability and inertness in human serum comparable to the corresponding DOTA complexes. The bispidine-based complexing agent was conjugated to a peptide, targeting somatostatin type 2 receptors (SSTR2), overexpressed on neuroendocrine tumors. The 177Lu- and 225Ac-labeled conjugates were investigated, considering their binding to two different SSTR2-positive cell lines, including the human pancreatic carcinoid tumor (BON-SSTR2+) and the murine pheochromocytoma cell line (MPC). The biodistribution and accumulation pattern in MPC tumor-bearing mice was also evaluated. The LuIII and AcIII complexes studied show how ligand structures can be optimized in general by extending the denticity and varying the donor set in order to allow for fast complex formation and medically relevant inertness.

Bispidine Chelators for Radiopharmaceutical Applications with Lanthanide, Actinide, and Main Group Metal Ions

“…The first protonation at a pK a value of 11.31 corresponds to the protonation of one of the tertiary amines of the bispidine backbone, while the other remains protonated in the accessible pH range. 32,34,36 Scheme 2. Synthetic Route to L 3 The next pK a values can be attributed to the protonation of the nitrogen donors at the pyridine groups (pK a = 7.57), the nitrogen of the picolinic acid (pK a = 4.58), and the carboxylic acid of the picolinic acid group (pK a = 3.30).…”

“…Labeling with [ 225 Ac]AcCl 3 (A = 50 kBq) shows quantitative complex formation up to 10 −6 M ligand, while the RCY for the labeling with [ 133 La]LaCl 3 (A = 10 MBq) already decreases significantly at a 10-fold higher chelator concentration. 34 This might be due to other metal ions interfering with the radiolabeling, e.g., Ba 2+ , Al 3+ , or Pb 2+ , which occurs during the Radiolabeling experiments with [ 212 Pb]Pb(OAc) 2 show quantitative complex formation down to 10 −5 M (10 μmol/L) for the labeling of L 2 at 40 °C. As shown in Figure 6, the radiolabeling efficiency of L 2 is therefore intermediate between those of the "gold standard" TCMC and DOTA, and this is not unexpected on the basis of the solution chemistry with natural nonradioactive isotopes.…”

“…Even with Pb 2+ , the titration with L 3 is less efficient than with L 2 ; full reproducibility of the titration data was secured by longer than usual equilibration times (15 min). The first protonation at a p K a value of 11.31 corresponds to the protonation of one of the tertiary amines of the bispidine backbone, while the other remains protonated in the accessible pH range. ,, The next p K a values can be attributed to the protonation of the nitrogen donors at the pyridine groups (p K a = 7.57), the nitrogen of the picolinic acid (p K a = 4.58), and the carboxylic acid of the picolinic acid group (p K a = 3.30). On the basis of the titrations of the ligands, the distributions of various ligand species at different pH values are obtained (see panels a and b of Figure for L 2 and L 3 , respectively).…”

“…Optimal labeling conditions were investigated on the basis of previously reported [ 225 Ac]Ac 3+ labeling experiments with L 2 . Different amounts of chelator were incubated with ∼50 kBq of [ 212/213 Bi][BiI 5 ] 2– /[ 212/213 Bi][BiI 4 ] − in sodium ascorbate buffer (150 mM, pH 4.8) at ambient temperature (25 °C) for 5 min, ∼10 MBq of [ 133 La]LaCl 3 at 40 °C for 60 min, or ∼70 kBq of [ 212 Pb]Pb(OAc) 2 in sodium acetate (100 mM, pH 6) at 40 °C for 60 min (see Experimental Section for details).…”

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

“…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.…”