^99mTc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma‑2 Receptor Ligands for Tumor Imaging

We have designed and synthesized a series of cyclopentadienyl tricarbonyl rhenium complexes containing a 5,6-dimethoxyisoindoline or a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline pharmacophore as σ₂ receptor ligands. Rhenium compound <b>20a</b> possessed low nanomolar σ₂ receptor affinity (<i>K</i>_i = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D_2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [^99mTc]<b>20b</b> showed high uptake in a time- and dose-dependent manner in DU145 prostate cells and C6 glioma cells. In addition, this tracer exhibited high tumor uptake (5.92% ID/g at 240 min) and high tumor/blood and tumor/muscle ratios (21 and 16 at 240 min, respectively) as well as specific binding to σ receptors in nude mice bearing C6 glioma xenografts. Small animal SPECT/CT imaging of [^99mTc]<b>20b</b> in the C6 glioma xenograft model demonstrated a clear visualization of the tumor at 180 min after injection

^99mTc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma‑2 Receptor Ligands for Tumor Imaging

We have designed and synthesized a series of cyclopentadienyl tricarbonyl rhenium complexes containing a 5,6-dimethoxyisoindoline or a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline pharmacophore as σ₂ receptor ligands. Rhenium compound <b>20a</b> possessed low nanomolar σ₂ receptor affinity (<i>K</i>_i = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D_2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [^99mTc]<b>20b</b> showed high uptake in a time- and dose-dependent manner in DU145 prostate cells and C6 glioma cells. In addition, this tracer exhibited high tumor uptake (5.92% ID/g at 240 min) and high tumor/blood and tumor/muscle ratios (21 and 16 at 240 min, respectively) as well as specific binding to σ receptors in nude mice bearing C6 glioma xenografts. Small animal SPECT/CT imaging of [^99mTc]<b>20b</b> in the C6 glioma xenograft model demonstrated a clear visualization of the tumor at 180 min after injection

Novel Cyclopentadienyl Tricarbonyl ^99mTc Complexes Containing 1‑Piperonylpiperazine Moiety: Potential Imaging Probes for Sigma‑1 Receptors

We report the design, synthesis, and evaluation of a series of novel cyclopentadienyl tricarbonyl ^99mTc complexes as potent σ₁ receptor radioligands. Rhenium compounds 3-(4-(1,3-benzodioxol-5-ylmethyl)­piperazin-1-yl)­propylcarbonylcyclopentadienyl tricarbonyl rhenium (<b>10a</b>) and 4-(4-(1,3-benzodioxol-5-ylmethyl)­piperazin-1-yl)­butylcarbonylcyclopentadienyl tricarbonyl rhenium (<b>10b</b>) possessed high in vitro affinity for σ₁ receptors and moderate to high selectivity for σ₂ receptors and the vesicular acetylcholine transporter. Biodistribution studies in mice demonstrated high initial brain uptake for corresponding ^99mTc derivatives [^99mTc]<b>23</b> and [^99mTc]<b>24</b> of 2.94 and 2.13% injected dose (ID)/g, respectively, at 2 min postinjection. Pretreatment of haloperidol significantly reduced the radiotracer accumulation of [^99mTc]<b>23</b> or [^99mTc]<b>24</b> in the brain. Studies of the cellular uptake of [^99mTc]<b>23</b> in C6 and DU145 tumor cells demonstrated a reduction of accumulation by incubation with haloperidol, 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)­piperazine (SA4503), or 1,3-di-<i>o</i>-tolyl-guanidine (DTG). Furthermore, blocking studies in C6 glioma-bearing mice confirmed the specific binding of [^99mTc]<b>23</b> to σ₁ receptors in the tumor

^99mTc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma‑2 Receptor Ligands for Tumor Imaging

We have designed and synthesized a series of cyclopentadienyl tricarbonyl rhenium complexes containing a 5,6-dimethoxyisoindoline or a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline pharmacophore as σ₂ receptor ligands. Rhenium compound <b>20a</b> possessed low nanomolar σ₂ receptor affinity (<i>K</i>_i = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D_2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [^99mTc]<b>20b</b> showed high uptake in a time- and dose-dependent manner in DU145 prostate cells and C6 glioma cells. In addition, this tracer exhibited high tumor uptake (5.92% ID/g at 240 min) and high tumor/blood and tumor/muscle ratios (21 and 16 at 240 min, respectively) as well as specific binding to σ receptors in nude mice bearing C6 glioma xenografts. Small animal SPECT/CT imaging of [^99mTc]<b>20b</b> in the C6 glioma xenograft model demonstrated a clear visualization of the tumor at 180 min after injection

Novel Cyclopentadienyl Tricarbonyl Complexes of ^99mTc Mimicking Chalcone as Potential Single-Photon Emission Computed Tomography Imaging Probes for β‑Amyloid Plaques in Brain

Rhenium and technetium-99m cyclopentadienyl tricarbonyl complexes mimicking the chalcone structure were prepared. These complexes were proved to have affinity to β-amyloid (Aβ) in fluorescent staining on brain sections of Alzheimer’s Disease (AD) patient and binding assay using Aβ_1–42 aggregates, with <i>K</i>_i values ranging from 899 to 108 nM as the extension of conjugated π system. In vitro autoradiograpy on sections of transgenic mouse brain confirmed the affinity of [^99mTc]<b>5</b> (<i>K</i>_i = 108 nM). In biodistribution, all compounds showed good initial uptakes into the brain and fast blood clearance, while the decreasing of initial brain uptakes correspond to increasing of conjugation length, from 4.10 ± 0.38% ID/g ([^99mTc]<b>3</b>) to 1.11 ± 0.34% ID/g ([^99mTc]<b>5</b>). These small technetium-99m complexes (<500 Da) designed by an integrated approach provide encouraging evidence that development of a promising ^99mTc-labeled agent for imaging Aβ plaques in the brain may be feasible

Synthesis and Evaluation of Novel ¹⁸F Labeled 2‑Pyridinylbenzoxazole and 2‑Pyridinylbenzothiazole Derivatives as Ligands for Positron Emission Tomography (PET) Imaging of β‑Amyloid Plaques

A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel β-amyloid (Aβ) imaging probes for PET. They displayed binding affinities for Aβ_1–42 aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for ¹⁸F labeling. In vitro autoradiography results confirmed the high affinity of these radiotracers. In vivo biodistribution experiments in normal mice indicated that the radiotracers with a short FPEG chain (<i>n</i> = 1) displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [¹⁸F]-5-(5-(2-fluoroethoxy)­benzo­[<i>d</i>]­oxazol-2-yl)-<i>N</i>-methylpyridin-2-amine ([¹⁸F]<b>32</b>) (<i>K</i>_i = 8.0 ± 3.2 nM) displayed a brain_2min/brain_60min ratio of 4.66, which is highly desirable for Aβ imaging agents. Target specific binding of [¹⁸F]<b>32</b> to Aβ plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [¹⁸F]<b>32</b> is a promising Aβ imaging agent for PET and merits further evaluation in human subjects

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

We report the syntheses and evaluation of series of novel piperidine compounds with low lipophilicity as σ₁ receptor ligands. 8-(4-(2-Fluoroethoxy)­benzyl)-1,4-dioxa-8-azaspiro[4.5]­decane (<b>5a</b>) possessed high affinity (<i>K</i>_i = 5.4 ± 0.4 nM) for σ₁ receptors and selectivity for σ₂ receptors (30-fold) and the vesicular acetylcholine transporter (1404-fold). [¹⁸F]<b>5a</b> was prepared using a one-pot, two-step labeling procedure in an automated synthesis module, with a radiochemical purity of >95%, and a specific activity of 25–45 GBq/μmol. Cellular association, biodistribution, and autoradiography with blocking experiments indicated specific binding of [¹⁸F]<b>5a</b> to σ₁ receptors in vitro and in vivo. Small animal positron emission tomography (PET) imaging using mouse tumor xenograft models demonstrated a high accumulation in human carcinoma and melanoma. Treatment with haloperidol significantly reduced the accumulation of the radiotracer in tumors. These findings suggest that radiotracer with suitable lipophilicity and appropriate affinity for σ₁ receptors could be used for tumor imaging

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

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)-3<i>H</i>-spiro­[2-benzofuran-1,4′-piperidine] (<b>19</b>) possessed high σ₁ receptor affinity (<i>K</i>_i = 0.79 nM) and excellent σ₁/σ₂ subtype selectivity (350-fold) as well as high σ₁/VAChT selectivity (799-fold). The radiolabeled compound [¹⁸F]<b>19</b> was synthesized by substitution of the tosylate precursor <b>24</b> with [¹⁸F]­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 [¹⁸F]<b>19</b> 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 [¹⁸F]<b>19</b> to σ₁ receptors in vivo