Distinctive In Vivo Kinetics of the New σ1 Receptor Ligands (R)-(+)- and (S)-(–)-18F-Fluspidine in Porcine Brain

Brust, Peter; Deuther‐Conrad, Winnie; Becker, Georg; Patt, Marianne; Donat, Cornelius K.; Stittsworth, Shannon; Fischer, Steffen; Hiller, Achim; Wenzel, Barbara; Dukić-Stefanović, Sladjana; Hesse, Swen; Steinbach, Jörg; Wünsch, Bernhard; Lever, Susan Z.; Sabri, Osama

doi:10.2967/jnumed.114.137562

Cited by 24 publications

(35 citation statements)

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“…Faster clearance and greater specific binding was observed for the N-pyridinyl analog 18 F-4 than the N-benzyl analog 18 F-3. The spirocyclic piperidine series thus demonstrated promising properties to image S1R with PET based on their high selectivity toward S1R and good binding characteristics in rodents, pigs, and a preliminary human study (14,(16)(17)(18)(19). Here, we report the first PET imaging evaluation in nonhuman primates of 4 radioligands ( 18 F-1 through 18 F-4, Fig.…”

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confidence: 86%

“…Furthermore, it should have the requisite lipophilicity (Log D 5 1-3) to cross the blood-brain barrier (14). (R)-(1) and (S)-(-)- 18 Ffluspidine ( 18 F-1 and 18 F-2, respectively) demonstrated good S1R binding affinity and favorable kinetics when tested in rodents and pigs (15)(16)(17). Kranz et al (18) also evaluated 18 F-2 in 4 healthy human subjects for dosimetry calculations.…”

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confidence: 99%

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PET Imaging Evaluation of Four σ₁ Radiotracers in Nonhuman Primates

et al. 2017

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The σ receptors (S1Rs) are implicated in a variety of diseases including Alzheimer disease and cancer. Previous PET S1R radiotracers are characterized by slow kinetics or off-target binding that impedes their use in humans. Here, we report the first PET imaging evaluation in rhesus monkeys of 4 F-labeled spirocyclic piperidine-based PET radiotracers (F- to F-). Baseline scans for the 4 radiotracers were obtained on an adult male rhesus monkey. Blocking scans were obtained with the S1R-selective agonist SA4503 to assess binding specificity ofF- and F- Arterial input functions were measured, and binding parameters were determined with kinetic modeling analysis. In the rhesus brain, all 4 radiotracers showed high and fast uptake. Tissue activity washout was rapid forF- and F-, and much slower for F- and F-, in line with their respective in vitro S1R-binding affinities. Both the 1-tissue-compartment and multilinear analysis-1 kinetic models provided good fits of time-activity curves and reliable estimates of distribution volume. Regional distribution volume values were highest in the cingulate cortex and lowest in the thalamus for all radiotracers. F- showed greater differential uptake across brain regions and 3-fold-higher binding potential than F- SA4503 at the dose of 0.5 mg/kg blocked approximately 85% (F-) and 95% (F-) of radiotracer binding. TracersF- and F- displayed high brain uptake and fast tissue kinetics, with F- having higher specific binding signals than F- in the same monkey. Taken together, these data indicate that both F- and F- possess the requisite kinetic and imaging properties as viable PET tracers for imaging S1R in the human brain.

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PET Imaging Evaluation of Four σ₁ Radiotracers in Nonhuman Primates

et al. 2017

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“…In a pertinent example, the ( R )-(+)- and ( S )-(−)-enantiomers of the σ 1 receptor PET radioligand [ 18 F]-fluspidine have been prepared for detailed comparison [68]. These non-superimposable “mirror images” are shown in Fig.…”

Section: Sigma Receptors and Ligand Designmentioning

confidence: 99%

Tactics for preclinical validation of receptor-binding radiotracers

Lever

Fan

Lever

2017

Nuclear Medicine and Biology

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Introduction Aspects of radiopharmaceutical development are illustrated through preclinical studies of [125I]-(E)-1-(2-(2,3-dihydrobenzofuran-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA- BF-PE-PIPZE), a radioligand for sigma-1 (σ1) receptors, coupled with examples from the recent literature. Findings are compared to those previously observed for [125I]-(E)-1-(2-(2,3-dimethoxy-5-yl)ethyl)-4-(iodoallyl)piperazine ([125I]-E-IA-DM-PE-PIPZE). Methods Syntheses of E-IA-BF-PE-PIPZE and [125I]-E-IA-BF-PE-PIPZE were accomplished by standard methods. In vitro receptor binding studies and autoradiography were performed, and binding potential was predicted. Measurements of lipophilicity and protein binding were obtained. In vivo studies were conducted in mice to evaluate radioligand stability, as well as specific binding to σ1 sites in brain, brain regions and peripheral organs in the presence and absence of potential blockers. Results E-IA-BF-PE-PIPZE exhibited high affinity and selectivity for σ1 receptors (Ki = 0.43 ± 0.03 nM, σ2 / σ1 = 173). [125I]-E-IA-BF-PE-PIPZE was prepared in good yield and purity, with high specific activity. Radioligand binding provided dissociation (koff) and association (kon) rate constants, along with a measured Kd of 0.24 ± 0.01 nM and Bmax of 472 ± 13 fmol / mg protein. The radioligand proved suitable for quantitative autoradiography in vitro using brain sections. Moderate lipophilicity, Log D7.4 2.69 ± 0.28, was determined, and protein binding was 71 ± 0.3%. In vivo, high initial whole brain uptake, > 6% injected dose / g, cleared slowly over 24 h. Specific binding represented 75% to 93% of total binding from 15 min to 24 h. Findings were confirmed and extended by regional brain biodistribution. Radiometabolites were not observed in brain (1%). Conclusions Substitution of dihydrobenzofuranylethyl for dimethoxyphenethyl increased radioligand affinity for σ1 receptors by 16-fold. While high specific binding to σ1 receptors was observed for both radioligands in vivo, [125I]-E-IA-BF-PE-PIPZE displayed much slower clearance kinetics than [125I]-E-IA-DM-PE-PIPZE. Thus, minor structural modifications of σ1 receptor radioligands lead to major differences in binding properties in vitro and in vivo.

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“…It regulates several functional proteins including D1 and D2 receptors through oligomerization and is increasingly implicated in the pathophysiology of virtually all major central nervous system disorders 41,42 . Recently developed, highly selective tracers like (S)-(−)- and (R)-(+)-[ 18 F]fluspidine 43 appear to be suitable for σ1 receptor imaging in humans and are currently under clinical investigation as a promising drug treatment target.…”

Section: Pet Radiotracers That Have Enabled Imaging Of Neurotransmmentioning

confidence: 99%

News and views on in-vivo imaging of neurotransmission using PET and MRI

Sander

Hesse

2017

Q J Nucl Med Mol Imaging

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Distinctive In Vivo Kinetics of the New σ₁ Receptor Ligands (R)-(+)- and (S)-(–)-¹⁸F-Fluspidine in Porcine Brain

Cited by 24 publications

References 27 publications

PET Imaging Evaluation of Four σ₁ Radiotracers in Nonhuman Primates

PET Imaging Evaluation of Four σ₁ Radiotracers in Nonhuman Primates

Tactics for preclinical validation of receptor-binding radiotracers

News and views on in-vivo imaging of neurotransmission using PET and MRI

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Distinctive In Vivo Kinetics of the New σ1 Receptor Ligands (R)-(+)- and (S)-(–)-18F-Fluspidine in Porcine Brain

Cited by 24 publications

References 27 publications

PET Imaging Evaluation of Four σ1 Radiotracers in Nonhuman Primates

PET Imaging Evaluation of Four σ1 Radiotracers in Nonhuman Primates

Tactics for preclinical validation of receptor-binding radiotracers

News and views on in-vivo imaging of neurotransmission using PET and MRI

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Product

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Distinctive In Vivo Kinetics of the New σ₁ Receptor Ligands (R)-(+)- and (S)-(–)-¹⁸F-Fluspidine in Porcine Brain

PET Imaging Evaluation of Four σ₁ Radiotracers in Nonhuman Primates

PET Imaging Evaluation of Four σ₁ Radiotracers in Nonhuman Primates