[99mTc]-1,4,7,10-Tetraazacyclododecane tetramethylenephosphonic acid

Excerpt

Pathological conditions such as neoplastic diseases, metabolic disorders, infections, and cancers often result in metastases of the disease to the skeletal system. During the past 50 years, a variety of bone-seeking radiopharmaceuticals have been developed and evaluated to detect skeletal metastases by imaging (1-3) or as pain palliative agents in patients (4). The diagnostic radiochemicals, usually phosphate and phosphonate derivatives of compounds, are particularly useful to detect the metastasis because they localize avidly in the bone (5, 6). Most bone lesions have an elevated concentration of minerals (mostly calcium salts) that form a major part of the matrix surface area, and these lesions have a high affinity for and facilitate the adsorption of the bone imaging agents (1, 7). Compared to phosphates, the phosphonate compounds are more stable under in vivo conditions because the phosphate bond with oxygen in pyrophosphate (P-O-P) is easily cleaved by chemical or enzymatic action, whereas the phosphonate bond in the diphosphonate (P-C-P) is insensitive to enzymatic or chemical action (8). Because of its stability and long retention in the bone, radionuclide-labeled methylene diphosphonate and its derivatives are routinely used for bone imaging to detect fractures or to detect and treat osteomyelitis and cancer metastasis (9-11). Radioactive samarium (¹⁵³Sm) coupled to a tetraphosphonate (ethylenediamine-tetramethylenephosphonic acid (¹⁵³Sm-lexidronam)) is approved by the United States Food and Drug Administration for pain palliation as a result of cancer that has metastasized to the bone. Similarly, another tetraphosphonate, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP), was conjugated with radioactive bismuth (²¹²Bi, a γ emitter) and has been shown to be promising for the treatment of bone cancer under preclinical conditions (12).

In an effort to develop an imaging agent, Datta et al. (13) envisioned that DOTMP conjugated with radioactive technetium (^99mTc-DOTMP) could possibly be used for the early detection of bone cancer or metastasis with single-photon emission computed tomography (SPECT). In a preliminary study the radiolabeled compound was evaluated for bone scintigraphy in normal rabbits, and its biodistribution was investigated in normal BALB/c mice.