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Purpose <p>The 5-hydroxytryptamine 7 receptor (5-HT₇R) is overexpressed in glioblastoma and represents a promising imaging target. This study aimed to design, synthesize, and evaluate technetium-99m-labeled pyridylpiperazine derivatives as potential 5-HT₇R-targeted SPECT radiotracers.</p> Methods <p>Two ligand<b>s</b> (<b>8</b> and <b>12</b>) were synthesized and radiolabeled with the <i>fac</i>-[⁹⁹ᵐTc]Tc(CO)₃⁺ core. Radiochemical purity and stability were assessed by RP-HPLC and TLC. Lipophilicity (log D) was determined using the octanol/PBS method. In vitro binding and specificity were evaluated in U87 MG, SKOV-3, HT-29, and A549 cell lines, including blocking studies. Affinity parameters were obtained from saturation binding assays. In vivo biodistribution and imaging were conducted in normal mice and U87 MG xenograft models.</p> Results <p>Both radiotracers showed high radiochemical purity (&gt; 96%) and stability. They exhibited moderate lipophilicity (log D = 0.43 ± 0.07 and 0.72 ± 0.01). [⁹⁹ᵐTc]Tc(CO)₃-<b>8</b> demonstrated high and selective binding to U87 MG cells (K<sub>d</sub> = 3.1 ± 0.41 nM; Bmax = (5.76 ± 0.34)*104 fmol/(1.0*107 cells)), whereas [⁹⁹ᵐTc]Tc(CO)₃-<b>12</b> showed negligible binding. In vivo, [⁹⁹ᵐTc]Tc(CO)₃-<b>8</b> displayed rapid blood clearance, hepatobiliary and renal excretion, and detectable brain uptake. In tumor-bearing mice, it showed significant tumor accumulation (tumor-to-muscle ratio: 4.32 ± 0.97), which decreased upon receptor blocking. Tumors were clearly visualized at 60 and 120&#xa0;min post-injection.</p> Conclusions <p>[⁹⁹ᵐTc]Tc(CO)₃-<b>8</b> represents a potentially useful lead compound for further development of 5-HT₇R-targeted SPECT radiotracers for glioblastoma imaging, with favorable stability, specificity, and tumor uptake, warranting further development.</p>

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Technetium-99m Tricarbonyl Pyridylpiperazine Radiotracers Targeting 5-HT₇ Receptors for SPECT Imaging of Glioblastoma

  • 期刊论文

  • 发表日期：

    2026年6月23日

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  • Mohammad Javad Molavipordanjani,
  • Alireza Mardanshahi,
  • Abbas Raisi,
  • Yasin Valizadeh,
  • Sajjad Molavipordanjani

摘要

Purpose

The 5-hydroxytryptamine 7 receptor (5-HT₇R) is overexpressed in glioblastoma and represents a promising imaging target. This study aimed to design, synthesize, and evaluate technetium-99m-labeled pyridylpiperazine derivatives as potential 5-HT₇R-targeted SPECT radiotracers.

Methods

Two ligands (8 and 12) were synthesized and radiolabeled with the fac-[⁹⁹ᵐTc]Tc(CO)₃⁺ core. Radiochemical purity and stability were assessed by RP-HPLC and TLC. Lipophilicity (log D) was determined using the octanol/PBS method. In vitro binding and specificity were evaluated in U87 MG, SKOV-3, HT-29, and A549 cell lines, including blocking studies. Affinity parameters were obtained from saturation binding assays. In vivo biodistribution and imaging were conducted in normal mice and U87 MG xenograft models.

Results

Both radiotracers showed high radiochemical purity (> 96%) and stability. They exhibited moderate lipophilicity (log D = 0.43 ± 0.07 and 0.72 ± 0.01). [⁹⁹ᵐTc]Tc(CO)₃-8 demonstrated high and selective binding to U87 MG cells (Kd = 3.1 ± 0.41 nM; Bmax = (5.76 ± 0.34)*104 fmol/(1.0*107 cells)), whereas [⁹⁹ᵐTc]Tc(CO)₃-12 showed negligible binding. In vivo, [⁹⁹ᵐTc]Tc(CO)₃-8 displayed rapid blood clearance, hepatobiliary and renal excretion, and detectable brain uptake. In tumor-bearing mice, it showed significant tumor accumulation (tumor-to-muscle ratio: 4.32 ± 0.97), which decreased upon receptor blocking. Tumors were clearly visualized at 60 and 120 min post-injection.

Conclusions

[⁹⁹ᵐTc]Tc(CO)₃-8 represents a potentially useful lead compound for further development of 5-HT₇R-targeted SPECT radiotracers for glioblastoma imaging, with favorable stability, specificity, and tumor uptake, warranting further development.