68Ga]/[188Re] Complexed [CDTMP] Trans-1,2-Cyclohexyldinitrilotetraphosphonic Acid As a Theranostic Agent for Skeletal Metastases.

Surbhi Prakash,Ankita Pandey,Ambika P Jaswal,Anil K Mishra,Virendra K Meena,Baljinder Singh,Puja P Hazari

doi:10.3389/fmed.2017.00072

Abstract

Metastasis of the osseous tissue is one of the frequent and severe aggravations as a result of several neoplastic conditions, such as metabolic disorders, infections, and cancer. The objective of this study was to evaluate the pertinence of [68Ga]-trans-1,2-cyclohexyldinitrilo tetramethylene phosphonic acid (CDTMP) as a potential bone imaging agent for positron emission tomography (PET) applications as well as to assess [188Re]-CDTMP for bone pain palliation in metastatic skeletal disorders. 68Ga complex of CDTMP was prepared at 80°C at pH 3.5, and 188Re complex of CDTMP was prepared at room temperature. [68Ga]-CDTMP complex was investigated as PET tracer while the therapeutic efficacy was assessed for [188Re]-CDTMP. Labeling efficiency, biodistribution, myelotoxicity, and imaging studies were carried out for the complexes synthesized. Both PET and MicroPET imaging studies were performed for [68Ga]-CDTMP whereas SPECT acquisitions were acquired for [188Re]-CDTMP. Data were analyzed semiquantitatively for all the scintigraphic scans obtained. The radiolabeling efficiency was observed to be >70% for [68Ga]-CDTMP. High bone uptake of [68Ga]-CDTMP as compared to contralateral tissue was found in PET imaging in Balb/C mice and New Zealand rabbit; the similar result for bone uptake was correlated in the biodistribution study of the compound in BALB/c mice at different time intervals. Biodistribution experiments carried out in mice showed maximum uptake of 6.12 ± 1.22%ID/g at 45 min postinjection. For [188Re]-CDTMP, total skeletal uptake was 8.12 ± 1.11%ID/g observed at 1 h postinjection from biodistribution data. High renal uptake confirms renal route of excretion. A good hydroxyapatite binding too was seen for both the complexes. No evidence of destruction or adverse functioning of vital organs was observed for the 188Re complex. [68Ga]-CDTMP complex can be used as a promising PET bone imaging agent and [188Re]-CDTMP as a surrogate moiety for therapeutic application. Owing to the short half-life of 68Ga (68 min), cyclotron-independent radiopharmacy, fast clearance, and rapid renal excretion as evidenced in preclinical animal models. Very low myelotoxicity and highly selective bone uptake prove the potential of [188Re]-CDTMP for therapeutic application.

Highlights

Abnormal growth associated with neoplastic conditions, such as anomalous metabolic disorders, contagions, and malignancies result in metastasis in the skeletal tissue
Before radiocomplexation of CDTMP, cold complexation of CDTMP was performed with cold gallium nitrate, which was characterized by mass spectroscopy
Development of [68Ga]-labeled bone-seeking agents could lead to further improvement in bone imaging using positron emission tomography (PET) independent of cyclotron-based radiopharmacy

Summary

Introduction

Abnormal growth associated with neoplastic conditions, such as anomalous metabolic disorders, contagions, and malignancies result in metastasis in the skeletal tissue. Bone metastasis is prevalent among the majority of patients with metastatic conditions, which results in a high percentage of mortality and morbidity. These skeletal-related events that involve hypercalcemia caused by malignancy, pathological fractures, etc., and arises the requirement for surgical intervention or radiation treatment in bone. Radiolabeled phosphonates are of utmost interest in nuclear medicine for metastasis evaluation as well as for therapy as many common tumors are associated with metastasis. Bone-targeting radiopharmaceuticals labeled with β emitters are acceptable adjuvant to external beam therapy for treatment of bone pain in osteoblastic bone metastatic condition. A therapeutic agent employed in radionuclide therapy consists of two components; α particle, β particle or Auger electron-emitting radioisotope and the molecular targeting vector that ensures maximum accumulation at or in desired tumor cells [7]

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