A new bisphosphonate-containing 99mTc(I) tricarbonyl complex potentially useful as bone-seeking agent: synthesis and biological evaluation

Abstract

Aiming to develop new bone-seeking radiotracers based on the organometallic core fac-[(99m)Tc(CO)(3)](+) with improved radiochemical and biological properties, we have prepared new conjugates with phosphonate pendant groups. The conjugates comprise a chelating unit for metal coordination, which corresponds to a pyrazolyl-containing backbone (pz) with a N,N,N donor-atom set, and a pendant diethyl phosphonate (pz-MPOEt), phosphonic acid (pz-MPOH) or a bisphosphonic acid (pz-BPOH) group for bone targeting. Reactions of the conjugates with the precursor [(99m)Tc(H(2)O)(3)(CO)(3)](+) yielded (mote than 95%) the single and well-defined radioactive species [(99m)Tc(CO)(3)(kappa(3)-pz-MPOEt)](+) (1a), [(99m)Tc(CO)(3)(kappa(3)-pz-MPOH](+) (2a) and [(99m)Tc(CO)(3)(kappa(3)-pz-BPOH)](+) (3a), which were characterized by reversed-phase high-performance liquid chromatography . The corresponding Re surrogates (1-3), characterized by the usual analytical techniques, including X-ray diffraction analysis in the case of 1, allowed for macroscopic identification of the radioactive conjugates. These radioactive complexes revealed high stability both in vitro (phosphate-buffered saline solution and human plasma) and in vivo, without any measurable decomposition. Biodistribution studies of the complexes in mice indicated a fast rate of blood clearance and high rate of total radioactivity excretion, occurring primarily through the renal-urinary pathway in the case of complex 3a. Despite presenting moderate bone uptake (3.04 +/- 0.47% injected dose per gram of organ, 4 h after injection), the high stability presented by 3a and its adequate in vivo pharmacokinetics encourages the search for new ligands with the same chelating unit and different bisphosphonic acid pendant arms.

Preparation and evaluation of a radiogallium complex-conjugated bisphosphonate as a bone scintigraphy agent

“…Thus, we hypothesized that the bone affinity of technetium-99m labeled bisphosphonate would be increased by the design of a bisphosphonate in which the phosphonate groups do not coordinate with technetium-99m. To enable imaging at an earlier time after injection, we and other groups have designed technetium-99m complex-conjugated bisphosphonate compounds based on the concept of bifunctional radiopharmaceuticals [7][8][9][10]. As we expected, some of the novel technetium-99m complex-conjugated Ogawa et al 6/35 bisphosphonate compounds showed superior biodistribution compared with previous compounds.…”

Evaluation of novel 99mTc(I)-labeled homobivalent α-melanocyte-stimulating hormone analogs for melanocortin-1 receptor targeting

“…The synthesis of this complex has already been described but starting from a different synthon [44]. Briefly, pz(CO 2 H) (0.05 mg, 0.131 mmol) reacted with the organometallic precursor [Re(CO) 3 3 ]Br (0.05 mg, 0.13 mmol) in refluxing water for 18 h. After evaporation of the solvent, the resulting residue was purified by preparative RP-HPLC (220 nm, gradient A).…”

Synthetic Procedures Leading towards Aminobisphosphonates

“…These conjugates were synthesized as bone-specific estrogens in the hope that they will protect elderly women from bone loss resulting from osteoporosis. A derivative of raloxifene, a selective estrogen receptor or modulator, was obtained using a suitable acid chloride as substrate [137], whereas radioligands, which are selectively bound to bone tissue, have been synthesized by using DCC/HOBt (hydroxybenzotriazol) activation [138] and antibacterial bisphosphonated benzoxazinorifamycin prodrugs using EDCl (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide) [139].…”