1-(4-[¹⁸F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine: A Novel Suitable Radioligand with Low Lipophilicity for Imaging σ₁ Receptors in the Brain

Abstract

We have designed and synthesized novel piperazine compounds with low lipophilicity as σ receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine (10) possessed a low nanomolar σ receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ receptors (52-fold), and adenosine A, adrenergic α, cannabinoid CB, dopamine D, D, γ-aminobutyric acid A (GABA), NMDA, melatonin MT, MT, and serotonin 5-HT receptors. The corresponding radiotracer [F]10 demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [F]10 was observed to enter the brain. Positron emission tomography and magnetic resonance imaging confirmed suitable kinetics and a high specific binding of [F]10 to σ receptors in rat brain. Ex vivo autoradiography showed a reduced level of binding of [F]10 in the cortex and hippocampus of the senescence-accelerated prone (SAMP8) compared to that of the senescence-accelerated resistant (SAMR1) mice, indicating the potential dysfunction of σ receptors in Alzheimer's disease.

Piperazine skeleton in the structural modification of natural products: a review

“…The piperazine ring, an important class of N-heterocyclic bioactive natural products, is extensively present in biologically active compounds 1 . The piperazine scaffold has been recognised as a privileged structure in drug discovery and is widely distributed in biologically active compounds employed in several different therapeutic fields, including antitumor 2 , antibacterial 3 , anti-inflammatory 4 , antipsychotic 5,6 , anti-Alzheimer 7,8 , antifungal 9 , and antidiabetics 10 . The N-4 nitrogen of piperazine can be used as a basic amine, while the N-1 nitrogen can easily introduce hydrogen bond acceptors and hydrophobic groups through other heterocyclics without necessitating the addition of a stereocenter 11,12 .…”

Current status and future perspective of radiopharmaceuticals in China

“…Jia's group designed and synthesized a range of new 18 F-labeled compounds that show potential for imaging σ1 receptor, including benzylpiperazine derivatives such as 1-(4-18 F-fluorobenzyl)-4-((tetrahydrofuran-2-yl)methyl) piperazine [35], 4-phenylpiperidine-4-carbonitrile derivatives [36], 1,4-dioxa-8-azaspiro [4,5]decane derivatives [37], and 1-oxa-8-azaspiro [4.5]decane derivatives [38]. [ 18 F] FBFP was synthesized in one step from an iodonium ylide precursor, and it possesses higher regional non-displaceable binding potential (BPND) values across the brain regions compared with (S)-[ 18 F]fluspidine [39].…”

18F‐Labeled benzylpiperazine derivatives as highly selective ligands for imaging σ1 receptor with positron emission tomography

“…( S )‐[ 18 F]fluspidine is another promising radiotracer, which is currently used to image the σ 1 receptors in patients with major depressive disorders and Huntington´s disease . In the past decades, we have put our efforts in the development of selective σ 1 receptor radioligands from several chemical classes, including 1‐piperonylpiperazine derivatives, 1,4‐dioxa‐8‐azaspiro[4.5]decane derivatives, 4‐phenylpiperidine‐4‐carbonitrile derivatives, spirocyclic piperidine derivatives, and 4‐[(tetrahydrofuran‐2‐yl)methyl]piperazine derivatives . The aim of the present study was to continue our search for an optimal 18 F‐labeled benzylpiperazine derivative with 3‐phenyl‐1‐(piperazin‐1‐yl)propan‐1‐one, 5‐phenyl‐1‐(piperazin‐1‐yl)pentan‐1‐one, or 1‐(3‐phenylpropyl)piperazine moiety for PET imaging of σ 1 receptors.…”

“…The distance between the basic nitrogen atom and the “primary hydrophobic region” or the “secondary hydrophobic region” were 0.25 to 0.39 nm and 0.6 to 1.0 nm, respectively . Later, it appears that smaller moiety with less lipophilicity can also serve as the “primary hydrophobic region”, indicating that the “primary hydrophobic region” in Glennon's pharmacophore model is more flexible . It was reported that compound 1 possessed low nanomolar affinity for σ 1 receptors ( K i (σ 1 ) = 1.8 ± 0.2 nM) and high subtype selectivity ( K i (σ 2 ) = 637 ± 15 nM, K i (σ 2 )/ K i (σ 1 ) = 354) .…”