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Localization of CaSR antagonists in CaSR-expressing medullary thyroid cancer

Haiming Ding1, Adlina Mohd Yusof, Shankaran Kothandaraman

  • 1MD, Department of Surgery, 410 West 10th Avenue, N907 Doan Hall, Columbus, OH 43210. john.phay@osumc.edu.

The Journal of Clinical Endocrinology and Metabolism
|September 14, 2013
PubMed
Abstract

Insights

New calcium-sensing receptor (CaSR) antagonists show promise for imaging medullary thyroid cancer. These compounds preferentially localize to CaSR-expressing tumors, aiding in surgical localization and potential therapeutic development.

Area of Science:

  • Biomedical Imaging
  • Molecular Imaging
  • Radiopharmaceutical Development

Background:

  • Medullary thyroid cancer (MTC) and parathyroid glands overexpress the calcium-sensing receptor (CaSR).
  • Improved surgical outcomes for MTC and parathyroid diseases necessitate precise image-based localization.
  • Current imaging techniques may lack specificity for CaSR-expressing tissues.

Purpose of the Study:

  • To develop and validate CaSR antagonists for in vivo tumor localization.
  • To assess the targeted delivery of novel CaSR antagonists to CaSR-expressing tumors.
  • To establish the potential of these antagonists as imaging pharmaceuticals.

Main Methods:

  • Synthesis of novel CaSR calcilytic analogs, including compound 9.
  • In vitro assessment of antagonistic activity using immunoblots and ERK1/2 phosphorylation assays.
  • Radiolabeling of compound 9 with iodine-125 ((125)I) and evaluation in nude mice bearing MTC xenografts (TT and MZ-CRC-1).
  • Biodistribution studies to quantify radioactivity uptake in tumors and background tissues.

Main Results:

  • Two novel compounds, 9 and 11, demonstrated superior CaSR antagonistic activity compared to Calhex 231.
  • Radiolabeled (125)I-compound 9 exhibited a half-life of 9.9 hours in mice.
  • Significantly higher radioactivity uptake was observed in CaSR-expressing TT tumors compared to non-expressing MZ-CRC-1 tumors (0.39% vs 0.18% ID/g at 24 hours, P = .002).
  • Tumor-to-background ratios for TT tumors increased over time, indicating specific tumor targeting.

Conclusions:

  • Novel CaSR antagonists effectively inhibit CaSR function in vitro.
  • These compounds demonstrate preferential localization to CaSR-expressing tumors in vivo.
  • The developed CaSR antagonists serve as promising scaffolds for future imaging pharmaceutical development.

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