Development of a calcium-sensing receptor molecular imaging agent

作者：Yusof Adlina Mohd; Kothandaraman Shankaran; Zhang Xiaoli; Saji Motoyasu; Ringel Matthew D; Tweedle Michael F; Phay John E^*

来源：Surgery, 2013, 154(6): 1378-1384.

DOI：10.1016/j.surg.2013.06.044

Background. Calcium-sensing receptor (CaSR) is expressed by parathyroid cells and thyroid C-cells (from which medullary thyroid carcinoma [MTC] is derived). A molecular imaging agent localizing to the CaSR could improve the detection of parathyroids and MTC preoperatively or intraoperatively. We synthesized a novel compound containing a fluorine residue for potential future labeling and demonstrated that the compound inhibited CaSR function in vitro.
Methods. We synthesized compound M, a derivative of a known calcilytic compound, Calhex-231. Human embryonic kidney cells transfected with green-fluorescent protein-tagged CaSR or control vector were preincubated with compound M before the addition of calcium. Immunoblotting for total mitogen-activated protein kinase (MAPK: ERK1/2), activated MAPK (phosphorylated ERK1/2), and glyceraldehyde 3-phosphate dehydrogenase was performed.
Results. Synthesis of compound M was confirmed by mass spectrometry. Inhibition of the MAPK signaling pathway by compound M was demonstrated in a dose-dependent manner by a decrease in phosphorylated EEK1/2 with no change in total ERK1/2 levels. Compound M inhibited MAPK signaling slightly better than the parent compound.
Conclusion. We have developed a novel molecule which demonstrates functional inhibition of CaSR and has a favorable structure for labeling. This compound appears to be appropriate for further development as a molecular imaging tool to enhance the surgical treatment of parathyroid disease and MTC.

• 出版日期2013-12