Synthesis and biological evaluation of two novel 99mTc cyclopentadienyl tricarbonyl complexes for sigma-1 receptor imaging


Synthesis and biological evaluation of two novel 99mTc cyclopentadienyl tricarbonyl complexes for sigma-1 receptor imaging

Wang, X.; Li, Y.; Deuther-Conrad, W.; Li, D.; Cui, M.; Steinbach, J.; Brust, P.; Liu, B. L.; Jia, H. M.

Objectives: Sigma-1 (σ1) receptors represent a distinct class of intracellular membrane proteins. The σ1 receptors are believed to be linked to a number of human diseases, including brain disorders, tumors and heart failure [1-3]. There are considerable interests in the development of 99mTc radiopharmaceuticals for imaging σ1 receptors using SPECT because of the routine availability of 99mTc radioisotope in hospitals and its ideal nuclear decay properties. We report the design, synthesis and biological evaluation of two novel 99mTc cyclopentadienyl tricarbonyl complexes for sigma-1 receptor imaging.

Methods: The synthetic routes of 99mTc labeled complexes and the corresponding rhenium complexes are shown in Scheme 1 [4]. The biological properties of the complexes were investigated by in vitro competition binding assays, biodistribution and inhibition studies in ICR mice.

Scheme 1. Synthetic routes of 99mTc labeled complexes and the corresponding rhenium complexes. Reagents and conditions: (a) 1, KI, toluene, TEA, 115 ºC, 4 h; (b) 2, KI, toluene, TEA, 115 ºC, 4 h; (c) 99mTc O4 -, Mn(CO)5Br, DMF, 140 ºC, 1 h.

Results: In vitro competition binding assays showed that rhenium complex 5 exhibited nanomolar affinity for σ1 receptors (Ki = 6.77 ± 4.56 nM) and low subtype selectivity (σ2 receptor: Ki = 26.7 ± 0.42 nM; Kiσ2/Kiσ1 = 3.94). Rhenium complex 6 possessed low nanomolar affinity for σ1 receptors (Ki = 2.11 ± 1.36 nM) and moderate subtype selectivity (σ2 receptor: Ki = 30.7 ± 3.83 nM ; Kiσ2/Kiσ1 = 14.5). [99mTc]9 and [99mTc]10 were prepared in 59 ± 2% and 62 ± 5% isolated radiochemical yields with radiochemical purity of >99% via double-ligand transfer (DLT) reaction from the corresponding ferrocene precursors. The log D values of [99mTc]9 and [99mTc]10 were determined to be 2.53 ± 0.09 and 2.24 ± 0.02, respectively. Biodistribution studies in mice revealed high initial brain uptakes of [99mTc]9 and [99mTc]10 with 1.95 ± 0.09 %ID/g and 2.94 ± 0.41 %ID/g at 2 min postinjection, respectively. The brain-to-blood ratios of [99mTc]10 were high with 3.02, 2.89, and 3.18 at 30 min, 1 h, and 4 h postinjection, respectively. Administration of haloperidol 5 min prior to injection of [99mTc]10 significantly reduced the radiotracer uptake in brain and spleen by 40-50% at 1 h postinjection, suggesting that the binding of [99mTc]10 to σ receptors was specific in vivo.

Conclusions: These findings suggest that [99mTc] warrants further investigation as putative sigma-1 receptor imaging agent.

Acknowledgements: Supported by NSFC (21071023).

References: [1] Hayashi T, et al (2011) Expert Opin Ther Targets, 15, 557-77. [2] Megalizzi V, et al (2012) Med Res Rev 32, 410-27. [3] Ito K, et al (2012) Cardiovasc Res, 93, 33-40. [4] Chen X, et al (2012) Bioorg Med Chem Lett, 22, 6352-57.

  • Lecture (Conference)
    The 20th International Symposium on Radiopharmaceutical Sciences - ISRS2013, 12.-17.05.2013, Jeju, South Korea
  • Abstract in refereed journal
    Journal of Labelled Compounds and Radiopharmaceuticals 56(2013), S77-S77
    ISSN: 0362-4803

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Publ.-Id: 18258