Bisphosphonates as radionuclide carriers for imaging or systemic therapy

Abstract

Bisphosphonates (BP's), biologically stable analogs of naturally occurring pyrophosphates, became the treatment of choice for pathologic conditions characterized by increased osteoclast-mediated bone resorption, namely Paget's disease, osteoporosis and tumor bone disease. Moreover, the clinical success of BP's is also associated with their use in (99m)Tc-based radiopharmaceuticals for bone imaging. In addition to the successful delivery of (99m)Tc (γ-emitter) to bone, BP's have also been used to deliver β(-)-particle emitting radiometals (e.g.(153)Sm, (186/188)Re) for bone-pain palliation. The main goal of this Review is to update the most recent research efforts toward the synthesis, characterization and biological evaluation of novel BP-containing radiometal complexes and radiohalogenated compounds for diagnostic or therapeutic purposes. The structure and in vivo properties of those compounds will be discussed and compared to the clinically available ones, namely in terms of image quality and therapeutic effect. We will also mention briefly the use of BP's as carriers of multimodal nuclear and optical imaging probes.

Formulation and evaluation of freeze-dried DOTMP kit for the preparation of clinical-scale 177Lu-DOTMP and 153Sm-DOTMP at the hospital radiopharmacy

“…A large number of patients suffering from cancers develop disseminated skeletal metastases at the advanced stage of their disease [1][2][3]. It is reported that ∼ 80% of these patients experience severe bone pain, which is the most common symptom manifested in metastatic skeletal carcinoma [4].…”

“…It is reported that ∼ 80% of these patients experience severe bone pain, which is the most common symptom manifested in metastatic skeletal carcinoma [4]. In addition to excruciating pain, other associated complications such as loss of mobility, skeletal fractures, hypercalcemia and spinal cord or nerve root compression severely impair the quality of life experienced by these patients [1][2][3][4][5][6]. Such patients are subjected to palliative care with the primary objective being alleviation of the pain resulting in improvement of the quality of life [7].…”

A comparative study of trans- and cis-isomers of a bone-seeking agent, DO2A2P

“…Despite the well-established clinical use, directly radiolabeled bisphosphonate complexes suffer several obvious limitations, which include low kinetic stability, suboptimal specific radioactivity, nonspecific accumulation in non-target tissues, and unknown coordination structure. 2 Therefore, significant efforts have been seen to develop bone seeking agents derivatized from bisphosphonates, in which the radiometal is coordinated by a “bifunctional chelator” that oftentimes carries a spacer to optimize the biological behavior. 2 In this regard, macrocyclic chelators are preferred over their acyclic counterparts because more kinetically stable complexes can result from their rigid and pre-organized structures.…”

“…2 Therefore, significant efforts have been seen to develop bone seeking agents derivatized from bisphosphonates, in which the radiometal is coordinated by a “bifunctional chelator” that oftentimes carries a spacer to optimize the biological behavior. 2 In this regard, macrocyclic chelators are preferred over their acyclic counterparts because more kinetically stable complexes can result from their rigid and pre-organized structures. 3–6 Furthermore, macrocyclic ligands bearing a mixed set of phosphonate and carboxylate groups, such as TRITP, DOTP, DOA3P, and trans -DO2A2P (Figure 1), have been reported as novel bone targeting agents when labeled with radioisotopes (e.g.…”

“…68 Ga-DOTP, 153 Sm/ 166 Ho-TRITP, and 177 Lu-DOTP). 2 In this class of complexes, both the macrocyclic core and the peripheral phosphonate or carboxylate moieties contribute to the metal binding, while the phosphonate still maintains the desired bone targeting capability. It has been reported that a positive correlation exists between the bone uptake and the number of methylphosphonate pendent arms.…”