Synthesis and preliminary evaluation of novel [(Cp-R)M(CO)₃] (M = Re, ^99mTc) complexes as potent sigma-2 receptor ligands

Objectives: Sigma-2 (σ₂) receptors have been proposed to be the progesterone receptor membrane component 1 [1]. Progress in cancer biology has revealed that (σ₂) receptors are over-expressed in many types of cancer [2]. The expression of (σ₂) receptors is assumed to be a suitable biomarker of cellular proliferation in solid tumors [3]. In our previous work, we used PB28 as lead compound to design novel ^99mTc cyclopentadienyl tricarbonyl complex as putative agent for (σ₂) receptor tumor imaging [4]. In this abstract, RHM-1, another (σ₂) receptor selective ligand, was used as lead compound to design novel [(Cp-R)M(CO)₃] (M = Re, ^99mTc) complexes as potent (σ₂) receptor ligands. Synthesis and preliminary evaluation of these complexes are reported.

Methods: The synthetic routes of ^99mTc labeled complexes and the corresponding rhenium complexes are shown in Scheme 1. The affinities of the rhenium complexes towards (σ₁) and (σ₂) receptors were investigated by in vitro competition binding assays.

Scheme 1. Reagents and conditions: (a) 4-bromobutanoyl chloride, CH₂Cl₂, AlCl₃, 0 °C to rt, 4 h; (b) 6-bromohexanoyl chloride, CH₂Cl₂, AlCl₃, 0 °C to rt, 4 h; (c) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, KI, toluene, TEA, 115 °C, 5 h; (d) 5,6-dimethoxyisoindoline, KI, toluene, TEA, 115 °C, 5 h; (e) ^99mTcO₄ ^-, Mn(CO)₅, DMF, 140 °C, 1 h.

Results: In vitro competition binding assays showed that rhenium complexes exhibited moderate to high affinity for σ₂ receptors and moderate subtype selectivity. K_i values of complex 2a towards σ₁ and σ₂ receptors were 121 ± 9.55 nM and 20.9 ± 0.23 nM, respectively. K_i values of complex 2c towards σ₁ and σ₂ receptors were 28.0 ± 9.35 nM and 9.13 ± 3.06 nM, respectively. [^99mTc]5a and [^99mTc]5c were prepared with radiochemical purity of >99% via double-ligand transfer (DLT) reaction from the corresponding ferrocene precursors. The log D values of [^99mTc]5a and [^99mTc]5c were determined to be 2.60 ± 0.06 and 2.56 ± 0.08, respectively. Biodistribution and inhibition studies are in progress.

Conclusions: These results are encouraging for further exploration of Tc-labeled probes for σ₂ receptor imaging in vivo.

Acknowledgements: Supported by NSFC (21071023).

References: [1] Xu J, et al (2011) Nat Commun, DOI 10.1038/ncomms 1386. [2] Megalizzi V, et al (2012) Med Res Rev, 32, 410-27. [3] Mach RH, et al (2009) Cent Nerv Syst Agents Med Chem, 9, 230-45. [4] Chen X, et al (2012) Bioorg Med Chem Lett, 22, 6352-57.