This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal is focused on the synthesis of novel macrocyclic bone-seeking agents with methylenephosphonate or bisphosphonate motif and their applications to noninvasive imaging of bone metastases. Currently the diagnostic imaging of bone metastases is commonly performed with 99mTc-MDP (methylene bisphosphonate). Due to the lack of high specificity and sensitivity, 99mTc-MDP bone scan is often aided by other imaging modalities, such as radiography, MRI, CT, PET scans, and/or bone marrow biopsy, for a final diagnosis. Recent pharmacological investigations have revealed that the mechanism of bisphosphonate anti-resorption effects on bone metastases involves two steps: bisphosphonates bind to hydroxyapatite bone mineral surface and subsequently are internalized by osteoclasts selectively where they inhibit the osteoclastic activity. The long retention of bisphosphonates with hydroxyapatite in the first step of the mechanism limits the specificity and sensitivity of a 99mTc-MDP bone scan for early detection of bone metastases due to the limited in vivo stability of the complex and the short half-life of 99mTc (t1/2 = 6.01 h). Based upon the pharmacological mechanism of bisphosphonates, we propose to address the hypothesis that the sensitivity and specificity of bone metastasis detection will be significantly improved if bone-seeking macrocyclic tetraamine complexes can be utilized for multimodality imaging diagnosis of bone metastases . It is well-known that macrocyclic chelators form kinetically more stable metal complexes than acyclic ligands. DO1A3P and DO2A2P are designed to form kinetically stable complexes with 177Lu (t1/2 = 6.71 d) and Gd(III) while the methylenephosphonate moieties are for osteoclast-targeting. DO3A-BP is hybrid ligand featuring both bisphosphonate (targeting osteoclasts) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), a traditional chelator used in metal radiopharmaceuticals and MRI contrast agents. Their chelates with radionuclides (64Cu: t1/2 = 12.7 h;and 177Lu: t1/2 = 6.71 d) will provide nuclear bone imaging agents with a wide range of radioactive half lives, which enables not only the detection/monitoring of bone metastases but also the mechanistic studies of bone abnormalities. In addition, we hypothesize that these same bone-seeking chelators will form stable complexes with Gd(III), which endows them with potential applications as magnetic resonance imaging (MRI) bone contrast agents as well. Both goals will advance the development of in vivo cancer imaging agents to improve the detection and diagnosis of bone metastases, and potentially provide novel imaging/palliative/therapeutic agents for the treatment and management of cancer patients.
The specific aims are proposed as follows:
Aim I. To synthesize and characterize bone-seeking macrocyclic chelators with a methylene-phosphonate or bisphosphonate motif and investigate their coordination chemistry with Cu(II), Lu(III), and Gd(III) The goal of this aim is to synthesize and characterize the bone-seeking ligand chelators (DO1A3P, DO2A2P, and DO3A-BP and obtain adequate amounts (~ 1 g) for follow-up studies. The complexes of proposed ligands with Cu(II), Lu(III), and Gd(III) will be prepared, characterized, and evaluated for their kinetic and thermodynamic stability in aqueous solution.
Aim II. To prepare and evaluate 64Cu and 177Lu labeled complexes as PET/SPECT imaging agents specifically for the detection and in situ monitoring of bone metastases The objective of this aim is to establish radiochemical protocols for the preparation of the bone-seeking radiopharmaceuticals, evaluate their in vivo stability and tissue uptake and clearance, and assess their potential applicability as PET/SPECT bone imaging agents as compared to 99mTc-MDP, the current clinical bone-scan agent. The most promising candidates will be tested using small animal PET and small animal SPECT in an intra-osseous bone metastasis model of prostate cancer xenografts in mice. Osteoclast-targeting evaluation will be performed to preliminarily evaluate the specificity of our proposed complexes to bone metastases.
Aim III. To prepare and investigate cold gadolinium complexes and identify optimal candidates as MRI bone-contrast agents for diagnostic imaging of bone metastases This aim is to test the hypothesis that the proposed bone-seeking chelators will form stable complexes with gadolinium, which can be used as MRI bone contrast agents as well. The gadolinium compounds will be evaluated as MRI bone-contrast agents for diagnostic imaging of bone metastases in the same bone metastasis model as in Aim II. We hope to identify candidates that give prolonged high contrast enhancement selectively at the bone-tissue interface, thus aiding bone imaging and enabling the use of MRI to study changes in bone structure with progression of bone metastases.
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