19 research outputs found
Desmethyl SuFEx-IT: SO<sub>2</sub>F<sub>2</sub>âFree Synthesis and Evaluation as a Fluorosulfurylating Agent
Access to SuFExable
compounds was remarkably simplified by introduction
of the solid FO2S-donor SuFEx-IT. However, the published
process for preparation of this reagent relies on the use of sulfuryl
fluoride (SO2F2), which is difficult to obtain
and highly toxic. Herein, we disclose a simple protocol for SO2F2-free, hectogram-scale preparation of the analogous
desmethyl SuFEx-IT from inexpensive starting materials. The reagent
was prepared in a high (85%) total yield and without chromatographic
purification steps. In addition, we demonstrate the utility of desmethyl
SuFEx-IT by successful preparation of a series of fluorosulfates and
sulfamoyl fluorides in high to excellent yields. As such, our work
recognizes desmethyl SuFEx-IT as a valuable alternative to common
FO2S-donors and enables cost-efficient access to substrates
for SuFEx click chemistry
Novel CDTA-based, Bifunctional Chelators for Stable and Inert Mn<sup>II</sup> Complexation: Synthesis and Physicochemical Characterization
In the search for
Mn<sup>II</sup> MR and PET/MR imaging agents with optimal balance
between thermodynamic stability, kinetic inertness, and relaxivity,
two novel bifunctional Mn<sup>II</sup> chelators (BFMnCs) based on
CDTA (<i>trans</i>-1,2-diaminocyclohexane-N,N,Nâ˛,Nâ˛-tetraacetic
acid) were synthesized. A six-step synthesis, involving the buildup
of a functionalized <i>trans</i>-1,2-diaminocyclohexane
core, provided CuAAC-reactive <b>6a</b> and <b>6b</b> bearing
an alkyne or azide substituent on the cyclohexane ring, respectively
(CuAAC = Cu<sup>I</sup>-catalyzed azideâalkyne 1,3-dipolar
cycloaddition). Thermodynamic, kinetic, and relaxometric studies were
performed with 4-HET-CDTA (<b>8a</b>) as a âmodel chelator,â
synthesized in two steps from <b>6a</b>. The protonation constants
revealed that <b>8a</b> is slightly less basic than CDTA and
forms a Mn<sup>II</sup> complex of marginally lower thermodynamic
stability (log <i>K</i><sub>MnL</sub> = 13.80 vs 14.32,
respectively), while the conditional stability constant is almost
identical for both chelates (pMn = 8.62 vs 8.68, respectively). Kinetic
assessment of the Cu<sup>II</sup>-mediated transmetalation of [MnÂ(4-HET-CDTA)]<sup>2â</sup> showed that proton-assisted complex dissociation
is slightly slower than for [MnÂ(CDTA)]<sup>2â</sup> (<i>k</i><sub>1</sub> = 297 vs 400 M<sup>â1</sup> s<sup>â1</sup>, respectively). Importantly, the dissociation half-life near physiological
conditions (pH 7.4, 25 °C) underlined that [MnÂ(4-HET-CDTA)]<sup>2â</sup> is âź35% more inert (<i>t</i><sub>1/2</sub> = 16.2 vs 12.1 h, respectively). Those findings may be
accounted for by a combination of reduced basicity and increased rigidity
of the ligand. Analysis of the <sup>17</sup>O NMR and <sup>1</sup>H NMRD data attributed the high relaxivity of [MnÂ(4-HET-CDTA)]<sup>2â</sup> (<i>r</i><sub>1</sub> = 4.56 mM<sup>â1</sup> s<sup>â1</sup> vs 3.65 mM<sup>â1</sup> s<sup>â1</sup> for [MnÂ(CDTA)]<sup>2â</sup>; 20 MHz, 25 °C) to slower
rotational dynamics (Ď<sub>R</sub><sup>298</sup> = 105 ps).
Additionally, the fast water exchange of the complex correlates well
with the value reported for [MnÂ(CDTA)]<sup>2â</sup> (<i>k</i><sub>ex</sub><sup>298</sup> = 17.6 Ă 10<sup>7</sup> vs 14.0 Ă 10<sup>7</sup> s<sup>â1</sup>, respectively).
Given the exquisite compromise between thermodynamic stability, kinetic
inertness, and relaxivity achieved by [MnÂ(4-HET-CDTA)]<sup>2â</sup>, appropriately designed CuAAC-conjugates of <b>6a</b>/<b>6b</b> are promising precursors for the preparation of targeted,
bioresponsive, or high relaxivity manganese-based PET/MR tracers (<sup>52<i>g</i>/55</sup> Mn<sup>II</sup>) and MR contrast agents
(Mn<sup>II</sup>)
Discovery of 7â[<sup>18</sup>F]Fluorotryptophan as a Novel Positron Emission Tomography (PET) Probe for the Visualization of Tryptophan Metabolism in Vivo
Tryptophan and its metabolites are
involved in different physiological
and pathophysiological processes. Consequently, positron emission
tomography (PET) tracers addressing tryptophan metabolic pathways
should allow the detection of different pathologies like neurological
disorders and cancer. Herein we report an efficient method for the
preparation of fluorotryptophans labeled in different positions with <sup>18</sup>F and their biological evaluation. 4â7-[<sup>18</sup>F]ÂFluorotryptophans ([<sup>18</sup>F]ÂFTrps) were prepared according
to a modified protocol of alcohol-enhanced Cu-mediated radiofluorination
in 30â53% radiochemical yields. In vitro experiments demonstrated
high cellular uptake of 4â7-[<sup>18</sup>F]ÂFTrps in different
tumor cell lines. 4, 5-, and 6-[<sup>18</sup>F]ÂFTrps, although stable
in vitro, suffered from rapid in vivo defluorination. In contrast,
7-[<sup>18</sup>F]ÂFTrp demonstrated a high in vivo stability and enabled
a clear delineation of serotonergic areas and melatonin-producing
pineal gland in rat brains. Moreover 7-[<sup>18</sup>F]ÂFTrp accumulated
in different tumor xenografts in a chick embryo CAM model. Thus, 7-[<sup>18</sup>F]ÂFTrp represents a highly promising PET probe for imaging
of Trp metabolism
Discovery of 7â[<sup>18</sup>F]Fluorotryptophan as a Novel Positron Emission Tomography (PET) Probe for the Visualization of Tryptophan Metabolism in Vivo
Tryptophan and its metabolites are
involved in different physiological
and pathophysiological processes. Consequently, positron emission
tomography (PET) tracers addressing tryptophan metabolic pathways
should allow the detection of different pathologies like neurological
disorders and cancer. Herein we report an efficient method for the
preparation of fluorotryptophans labeled in different positions with <sup>18</sup>F and their biological evaluation. 4â7-[<sup>18</sup>F]ÂFluorotryptophans ([<sup>18</sup>F]ÂFTrps) were prepared according
to a modified protocol of alcohol-enhanced Cu-mediated radiofluorination
in 30â53% radiochemical yields. In vitro experiments demonstrated
high cellular uptake of 4â7-[<sup>18</sup>F]ÂFTrps in different
tumor cell lines. 4, 5-, and 6-[<sup>18</sup>F]ÂFTrps, although stable
in vitro, suffered from rapid in vivo defluorination. In contrast,
7-[<sup>18</sup>F]ÂFTrp demonstrated a high in vivo stability and enabled
a clear delineation of serotonergic areas and melatonin-producing
pineal gland in rat brains. Moreover 7-[<sup>18</sup>F]ÂFTrp accumulated
in different tumor xenografts in a chick embryo CAM model. Thus, 7-[<sup>18</sup>F]ÂFTrp represents a highly promising PET probe for imaging
of Trp metabolism
Data_Sheet_1_GABAA receptor availability relates to emotion-induced BOLD responses in the medial prefrontal cortex: simultaneous fMRI/PET with [11C]flumazenil.PDF
IntroductionThe fMRI BOLD response to emotional stimuli highlighting the role of the medial prefrontal cortex (MPFC) has been thoroughly investigated. Recently, the relationship between emotion processing and GABA levels has been studied using MPFC proton magnetic resonance spectroscopy (1H-MRS). However, the role of GABAA receptors in the MPFC during emotion processing remains unexplored.MethodsUsing [11C]flumazenil PET, we investigated the relationship between the binding potential of GABAA receptors and emotion processing as measured using simultaneous fMRI BOLD. We hypothesized a correlation between the percent signal change in the BOLD signal and the binding potential of GABAA receptors in the MPFC. In a combined simultaneous fMRI and [11C]flumazenil-PET study, we analyzed the data from 15 healthy subjects using visual emotional stimuli. Our task comprised two types of emotional processing: passive viewing and appraisal. Following the administration of a bolus plus infusion protocol, PET and fMRI data were simultaneously acquired in a hybrid 3 T MR-BrainPET.ResultsWe found a differential correlation of BOLD percent signal change with [11C]flumazenil binding potential in the MPFC. Specifically, [11C]flumazenil binding potential in the ventromedial prefrontal cortex (vMPFC) correlated with passive viewing of emotionally valenced pictures. In contrast, the [11C]flumazenil binding potential and the BOLD signal induced by picture appraisal did show a correlation in the paracingulate gyrus.ConclusionOur data deliver first evidence for a relationship between MPFC GABAA receptors and emotion processing in the same region. Moreover, we observed that GABAA receptors appear to play different roles in emotion processing in the vMPFC (passive viewing) and paracingulate gyrus (appraisal).</p
Correlation of striatal FDOPA-PET K<sub>i</sub> values with selected putaminal MRSI data given for all PINK1 mutation carriers (nâ=â11) and for individuals with heterozygous mutations only (nâ=â9).
<p>râ=âSpearman rank correlation coefficient; n.s.â=ânot significant.</p
<sup>1</sup>H MRSI data of the PINK1 study cohort compared to age-matched healthy controls.
<p>Data are given as mean (1SD). 95% CIâ=â95% confidence interval.</p
<sup>31</sup>P MRSI data of the PINK1 study cohort compared to age-matched healthy controls.
<p>Data are given as mean (1SD). 95% CIâ=â95% confidence interval. Bold data with an asterisk mark values outside of the 2SD range of controls.</p
Correlation of MRSI and PET findings in the putamen.
<p>Across the entire study cohort with either a single heterozygous (nâ=â9, open circles) or two homozygous PINK1 mutations (nâ=â2, black triangles), the mean putaminal FDOPA K<sub>i</sub> values (min<sup>â1</sup>) determined by PET correlated positively with MRSI-measured MI levels (râ=â0.879, p<0.001) (a), but inversely with ATP (râ=ââ0.784, pâ=â0.008) (b) and GPC concentrations (râ=ââ0.651, pâ=â0.030) (c). Spearman rank correlation, p-values give the significance level. The dashed horizontal lines set the upper and lower limits of the 2SD range in healthy controls. Note that we found concentrations above the upper limit for GPC in both and for ATP in one of the homozygous mutation carriers.</p
Calculated MRSI data of the PINK1 study cohort compared to age-matched healthy controls.
<p>Data are given as mean (1SD). 95% CIâ=â95% confidence interval. Bold data with an asterisk mark values outside of the 2SD range of controls.</p