Synthesis and pharmacological evaluation of ¹¹C-labeled piperazine derivative as a PET probe for sigma-2 receptor imaging.

Introduction: Both subtypes of sigma (σ) receptors, σ₁ and σ₂, are over-expressed in many cancers with σ₂ proposed as a biomarker of tumor proliferation. We are interested in developing a high affinity selective σ₂ radioligand for in vivo monitoring of proliferative status of solid tumors and response to anti-cancer therapies. 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) represents one of the lead candidates in the development of σ receptor ligands for therapeutic and diagnostic applications. However, the utility of PB28 is limited due to its relatively high lipophilicity.

Methods: A more hydrophilic analogue (-)-(S)-1 was radiolabeled with (11)C via standard O-alkylation. In vitro autoradiography with [(11)C](-)-(S)-1 was done using rat brain slices. PET imaging was performed in mice bearing EMT6, C6 or PC-3 tumors after i.v. injection of [(11)C](-)-(S)-1.

Results: [(11)C](-)-(S)-1 was produced in 53%±7% isolated decay-corrected yield with radiochemical and chemical purity over 99% and specific activity greater than 100 GBq/μmol. In vitro autoradiography with [(11)C(-)-(S)-1 resulted in a heterogeneous binding of the tracer in the rat brain with the highest radioactivity signals in the cortex region followed by cerebellum. This binding was successfully blocked by 10 μM of either haloperidol, (+)-(R)-1 or PB28. For C6 xenografts low target-to-nontarget ratio and high non-specific binding did not allow clear tumor visualization. No accumulation was visible in EMT6 tumor or in PC-3 tumor. Rat and mouse brain uptake was low and homogeneous while stronger signal was detected in the spinal cord. High accumulation of radioactivity was observed in liver and intestine suggesting hepatobiliary clearance.

Conclusions: Despite excellent in vitro properties, [(11)C](-)-(S)-1 did not provide high enough specific binding in vivo and is, therefore, not a useful PET tracer for imaging σ₂ expression in tumors.