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

Abstract

Octadentate and specifically nonadentate ligands with a bispidine scaffold (3,7-diazabicyclo[3.3.1]nonane) are known to be efficiently coordinated to a range of metal ions of interest in radiopharmaceutical chemistry and lead to exceedingly stable and inert complexes. Nonadentate bispidine L 2 (with a tridentate bipyridine acetate appended to N3 and a picolinate at N7) has been shown before to be an ideal chelator for 111In3+, 177Lu3+, and 225Ac3+, nuclides of interest for diagnosis and therapy, and a proof-of-principle study with an SSTR2-specific octreotate has shown potential for theranostic applications. We now have extended these studies in two directions. First, we present ligand derivative L 3 , in which the bipyridine acetate is substituted with terpyridine, a softer donor for metal ions with a preference for more covalency. L 3 did not fulfill the hopes because complexation is much less efficient. While for Bi3+ and Pb2+ the ligand is an excellent chelator with properties similar to those of L 2 , Lu3+ and La3+ show very slow and inefficient complexation with L 3 in contrast to L 2 , and 225Ac3+ is not fully coordinated, even at an increased temperature (92% radiochemical yield at 80 °C, 60 min, [L 3 ] = 10–4 M). These observations have led to a hypothesis for the complexation pathway that is in line with all of the experimental data and supported by a preliminary density functional theory analysis, which is important for the design of further optimized bispidine chelators. Second, the coordination chemistry of L 2 has been extended to Bi3+, La3+, and Pb2+, including solid state and solution structural work, complex stabilities, radiolabeling, and radiostability studies. All complexes of this ligand (La3+, Ac3+, Lu3+, Bi3+, In3+, and Pb2+), including nuclides for targeted α therapy (TAT), single-photon emission computed tomography, and positron emission tomography, are formed efficiently under physiological conditions, i.e., suitable for the labeling of delicate biological vectors such as antibodies, and the complexes are very stable and inert. Importantly, for TAT with 225Ac, the daughter nuclides 213Bi and 209Pb also form stable complexes, and this is important for reducing damage to healthy tissue.

Radiolabelled 177Lu‐Bispidine‐Trastuzumab for Targeting Human Epidermal Growth Factor Receptor 2 Positive Cancers

“…[18] Bisp displays fast radiolabelling under mild conditions with 177 Lu 3 + and 225 Ac 3 + ions [18,22] and also forms complexes with 133 La 3 + , 212/213 Bi 3 + and 212 Pb 3 + . [23] Metal ion complexes of Bisp with Pb 2 + , Lu 3 + , and La 3 + also showed a high degree of thermodynamic and kinetic stability, which are prerequisites in successful radiotracer design. In a proof-of-concept study, the Bisp was attached via classical bioconjugation methods by using a benzyl-NCS group to (Tyr 3 )octreotate, a somatostatin receptor subtype 2 (SSTR2 +) binding vector for specific targeting of neuroendocrine tumours of the gastrointestinal tract.…”

PYTA: a universal chelator for advancing the theranostic palette of nuclear medicine

“…S1 in the ESI†) were developed recently as dual-size-selective chelators for binding both large and small radioactive rare-earth ions, such as the Meitner–Auger-electron emitter lanthanum-135 ( 135 La 3+ , 8-coordinate ionic radius = 1.16 Å) 17 and the β + emitter scandium-44 ( 44 Sc 3+ , 8-coordinate ionic radius = 0.87 Å), 17 respectively. Several high denticity acyclic bispidine 18,19 and picolinic acid 20,21 chelators have also been identified to mutually stabilize the α-emitting radionuclide actinium-225 ( 225 Ac) and either indium-111 ( 111 In), a SPECT radionuclide, or lutetium-177 ( 177 Lu), a therapeutic β − emitter with imageable γ emissions (Fig. S1†).…”