Tc-Labeled 1-hydroxy-2-(2-isopropyl-1H-imidazole-1-yl)ethylidene-1,1-bisphosphonic acid

Bisphosphonates (BPs; also known as diphosphonates) labeled with technetium ([Tc]-BPs) are often used in bone scintigraphy to detect osteoporosis and other skeletal-related events (SREs), including bone metastases (1). These chemicals are known to promote osteoclast apoptosis and have a strong affinity for hydroxyapatite, a component of the bone matrix. The mechanism of action of these bone-seeking compounds is described in detail elsewhere (2-4). Bone scintigraphy is usually performed 2–6 h after intravenous injection of a [Tc]-BP, resulting in exposure of the patient to radiation for an extended time (due to slow clearance from circulation). To develop BPs that are more efficient and require only a short waiting time before bone scintigraphy, investigators generated various BPs, such as zoledronic acid (ZL), which contains an imidazole group in its structure, and evaluated their efficacy for the treatment of various bone-related diseases (5, 6). ZL was determined to be the most potent BP available for treating bone resorption and is approved by the United States Food and Drug Administration for the treatment of various tumor-induced SREs (7). In an earlier study to further improve the potency of ZL, the imidazole group of the compound was modified to obtain 1-hydroxy-2-(2-ethyl-4-methyl-1H-imidazole-1-yl)ethane-1,1-diyldiphosphonic acid (EMIDP), and the chemical was labeled with Tc to produce [Tc]-EMIDP (1). The biodistribution of [Tc]-EMIDP was investigated in normal mice, and the radiochemical was evaluated as a bone-imaging agent in rabbits. From these studies, the investigators concluded that [Tc]-EMIDP bound selectively to the skeletal tissue in rabbits with superior selectivity compared to that of Tc-labeled methylene diphosphonate ([Tc]-MDP), another BP that is commonly used in the clinic. In a effort to further explore the possibility of generating a high-potency ZL derivative similar to EMIDP, Lin et al. investigated optimization of the linker chain between the imidazolyl and the germinal BP group in the structure of ZL (8). For this, a ZL derivative, 1-hydroxy-3-(1H-imidazol-1-yl)propane-1,1-diyldiphosphonic acid was synthesized and labeled with Tc, and its biodistribution and bone-imaging properties (with single-photon emission computed tomography (SPECT) imaging) were investigated in normal mice and rabbits, respectively (8). As a continuation of this work, another ZL derivative with 2-isopropyl on the imidazole ring, 1-hydroxy-2-(2-isopropyl-1H-imidazole-1-yl)ethylidene-1,1-bisphosphonic acid (iPIDP), was prepared and labeled with Tc (to produce [Tc]-iPIDP), and the biodistribution of the labeled compound was investigated in mice (9). In addition, the investigators used SPECT to study the bone-imaging characteristics of [Tc]-iPIDP in rabbits.