Synthesis and preliminary evaluation of [18F]-fluoro-(2S)-Exaprolol for imaging cerebral β-adrenergic receptors with PET

Cerebral β-adrenergic receptors (β-ARs) are of interest in several disorders including Parkinson's disease, Alzheimer's disease and in particular major depressive disorder. Development of a positron emission tomography (PET) ligand for imaging β-ARs would allow the quantification of these receptors in the living human brain so as to better understand both the pathophysiology of depression and how to improve treatment. Currently there are no radioligands suitable for this purpose. In an attempt to achieve this goal, we prepared [18F]-labeled (2S)-1-(1-fluoropropan-2-ylamino)-3-(2-cyclohexylphenoxy)propan-2-ol (fluoro-Exaprolol; (2S)-1). Radiolabeling with fluorine-18 was accomplished via preparation of a precursor containing a tosyl leaving group (10), and utilizes the 2-oxazolidinone group to simultaneously protect both the amine and hydroxy groups. The oxazolidinone was readily removed with lithium aluminum hydride following a nucleophilic [18F]-fluoride for tosyl displacement to prepare [18F]-(2S)-1 in 31% radiochemical yield (uncorrected for decay), with >98% radiochemical purity in <1 h. The specific activity of the formulated product was 927 mCi/μmol and the log P (pH 7.4) was 2.97. Preliminary biological evaluations in conscious rats indicated that [18F]-(2S)-1 had good brain uptake for imaging (0.8–1.3% injected dose/gram (% ID/g) of wet tissue, 5 min post-injection of the radiotracer) with a slow washout (>0.5% ID/g at 60 min post-injection) in all brain regions. Pharmacological challenges indicate that the binding is largely non-specific, as administration of Propranolol, authentic (2S)-1, or WAY 100635 prior to injection of [18F]-(2S)-1 did not block uptake of the radiotracer. These results indicate that [18F]-(2S)-1 is not a suitable candidate for PET imaging of cerebral β-ARs.