Characterization of [¹⁸F]N-(9-(4-fluoroethylbenzyl)-9-aza-bicyclo[3.3.1]nonan-3α-yl)-N-(2-methoxy-5-methylphenyl)carbamate (1) as a potential σ2 receptor radiotracer for PET

Abstract

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Objectives: It has been demonstrated that the σ2 receptor is a potential receptor-based biomarker for imaging the proliferative status of solid tumors (Brit. J. Cancer 2000, 82: 1223). Therefore, radiotracers that target the σ2 receptor may be a good strategy for imaging the proliferative status of solid tumors using noninvasive imaging procedures such as positron emission tomography (PET). We have identified compound 1 as a selective σ2 receptor ligand. The K_i for σ1 is 1711 nM, K_i for σ2 is 0.82 nM and the σ1:σ2 is 2086. The goal of the current study is to evaluate [¹⁸F]1 as a radiotracer for imaging the σ2 receptor status of breast tumors.

Methods: The synthesis of [¹⁸F]1 was accomplished by heating the corresponding mesylate precursor with [¹⁸F]/fluoride. Biodistribution studies were conducted in BALB/c mice implanted subcutaneously in the scapular region with EMT-6 mammary tumor cells. Animals were injected in the tail vein with 20-25 μCi of the ¹⁸F-labeled radiotracer and were sacrificed at 5, 30, 60 and 120 min post-injection.

Results: [¹⁸F]1 was prepared in an overall yield of ~50% and a specific activity of ~4200 Ci/mmol. In vivo biodistribution studies indicate that there is a high uptake of the radiotracer in tumor at 5 min post-injection (1.39 ± 0.34 %ID/g). However, there was also a very high uptake of radioactivity in the lung (111.0 ± 13.5 %ID/g) at 5 min post-injection and a significant increase in the uptake of radioactivity in fat (12.6 ± 0.6 %ID/g) at 2 h post-injection. Although the compound showed favorable tumor:blood ratios, the tumor:fat ratio was less than 1.0 at all timepoints. These data suggest that formation of a radiolabeled lipophilic metabolite occurs which will preclude the use of [¹⁸F]1 as a radiotracer for imaging the σ2 receptor status of solid tumors.

Conclusions: In spite of its promising in vitro binding properties, [¹⁸F]1 is not a potential radiotracer for imaging the σ2 receptor status of solid tumors in vivo with PET.

Research Support (if any): Supported by CA102869 and DAMD 17-01-1-0446.