Synthesis and Evaluation of Novel ¹⁸F-Labeled Spirocyclic Piperidine Derivatives as σ₁ Receptor Ligands for Positron Emission Tomography Imaging

Abstract

A series of spirocyclic piperidine derivatives were designed and synthesized as σ1 receptor ligands. In vitro competition binding assays showed that 1'-(4-(2-fluoroethoxy)benzyl)-3H-spiro[2-benzofuran-1,4'-piperidine] (19) possessed high σ1 receptor affinity (Ki = 0.79 nM) and excellent σ1/σ2 subtype selectivity (350-fold) as well as high σ1/VAChT selectivity (799-fold). The radiolabeled compound [(18)F]19 was synthesized by substitution of the tosylate precursor 24 with [(18)F]fluoride, with an isolated radiochemical yield of 35-60%, a radiochemical purity of >99%, and a specific activity of 30-55 GBq/μmol. Biodistribution studies in imprinting control region mice indicated that [(18)F]19 displayed excellent initial brain uptake and slow washout. Ex vivo autoradiography in Sprague-Dawley rats demonstrated high accumulation of the radiotracer in brain areas known to express high levels of σ1 receptors. Micro positron emission tomography imaging and blocking studies confirmed the specific binding of [(18)F]19 to σ1 receptors in vivo.

18F-Labeled 1,4-Dioxa-8-azaspiro[4.5]decane Derivative: Synthesis and Biological Evaluation of a σ1 Receptor Radioligand with Low Lipophilicity as Potent Tumor Imaging Agent

“…Compound 8 was obtained from the reaction of p-cresol and 1-bromo-2-fluoroethane followed by radical bromination with a total yield of 39% according to the reported method in the literature. 35 N-alkylation of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1,4-dioxa-8-azaspiro [4.5]decane (9) gave compounds 5a-5e, 6a and 6b with yields of 39-87%. Reactions between compounds 10a-10d with the corresponding bromides provided compounds 7a-7h with yields of 42-69%.…”

“…35 Compound 9 (670 mg, 4.68 mmol) and The procedures for the radioligand competition assays of 5a-5e, 6a, 6b and 7a-7h were previously described. 35,40 Detailed procedures are presented in the Supporting Information.…”

“…35 Compound 9 (670 mg, 4.68 mmol) and The procedures for the radioligand competition assays of 5a-5e, 6a, 6b and 7a-7h were previously described. 35,40 Detailed procedures are presented in the Supporting Information. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 in the following tumor cell models using a protocol published elsewhere with some modifications.…”

“…34 to possess subnanomolar affinity and excellent selectivity towards σ 2 receptors and the vesicular acetylcholine transporter (VAChT). 35 It also exhibited high initial brain uptake and specific binding to σ 1 receptors in vivo. 35 Moreover, 1'-benzyl-3-methoxy-3,4-dihydrospiro(2-benzopyran-1,4'-piperidine) (1b) possessed high 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 affinity for σ 1 receptors and high subtype selectivity.…”

“…Determination of log D Value. Flask shake method with 1-octanol/phosphate-buffered saline (PBS, 0.05 mol/L, pH = 7.4) was applied to determine the log D value of [ 18 F]5aaccording to literature 35,40. The detailed procedure is shown in the Supporting Information.In Vitro Stability.…”