Desmethyl SuFEx-IT: SO₂F₂‑Free 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^II Complexation: Synthesis and Physicochemical Characterization

In the search for Mn^II MR and PET/MR imaging agents with optimal balance between thermodynamic stability, kinetic inertness, and relaxivity, two novel bifunctional Mn^II chelators (BFMnCs) based on CDTA (<i>trans</i>-1,2-diaminocyclohexane-N,N,N′,N′-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^I-catalyzed azide–alkyne 1,3-dipolar cycloaddition). Thermodynamic, kinetic, and relaxometric studies were performed with 4-HET-CDTA (<b>8a</b>) as a “model chelator,” 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^II complex of marginally lower thermodynamic stability (log <i>K</i>_MnL = 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^II-mediated transmetalation of [Mn­(4-HET-CDTA)]^2– showed that proton-assisted complex dissociation is slightly slower than for [Mn­(CDTA)]^2– (<i>k</i>₁ = 297 vs 400 M^–1 s^–1, respectively). Importantly, the dissociation half-life near physiological conditions (pH 7.4, 25 °C) underlined that [Mn­(4-HET-CDTA)]^2– is ∼35% more inert (<i>t</i>_1/2 = 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 ¹⁷O NMR and ¹H NMRD data attributed the high relaxivity of [Mn­(4-HET-CDTA)]^2– (<i>r</i>₁ = 4.56 mM^–1 s^–1 vs 3.65 mM^–1 s^–1 for [Mn­(CDTA)]^2–; 20 MHz, 25 °C) to slower rotational dynamics (τ_R²⁹⁸ = 105 ps). Additionally, the fast water exchange of the complex correlates well with the value reported for [Mn­(CDTA)]^2– (<i>k</i>_ex²⁹⁸ = 17.6 × 10⁷ vs 14.0 × 10⁷ s^–1, respectively). Given the exquisite compromise between thermodynamic stability, kinetic inertness, and relaxivity achieved by [Mn­(4-HET-CDTA)]^2–, 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 (^{52<i>g</i>/55} Mn^II) and MR contrast agents (Mn^II)

Discovery of 7‑[¹⁸F]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 ¹⁸F and their biological evaluation. 4–7-[¹⁸F]­Fluorotryptophans ([¹⁸F]­FTrps) were prepared according to a modified protocol of alcohol-enhanced Cu-mediated radiofluorination in 30–53% radiochemical yields. In vitro experiments demonstrated high cellular uptake of 4–7-[¹⁸F]­FTrps in different tumor cell lines. 4, 5-, and 6-[¹⁸F]­FTrps, although stable in vitro, suffered from rapid in vivo defluorination. In contrast, 7-[¹⁸F]­FTrp demonstrated a high in vivo stability and enabled a clear delineation of serotonergic areas and melatonin-producing pineal gland in rat brains. Moreover 7-[¹⁸F]­FTrp accumulated in different tumor xenografts in a chick embryo CAM model. Thus, 7-[¹⁸F]­FTrp represents a highly promising PET probe for imaging of Trp metabolism

Discovery of 7‑[¹⁸F]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 ¹⁸F and their biological evaluation. 4–7-[¹⁸F]­Fluorotryptophans ([¹⁸F]­FTrps) were prepared according to a modified protocol of alcohol-enhanced Cu-mediated radiofluorination in 30–53% radiochemical yields. In vitro experiments demonstrated high cellular uptake of 4–7-[¹⁸F]­FTrps in different tumor cell lines. 4, 5-, and 6-[¹⁸F]­FTrps, although stable in vitro, suffered from rapid in vivo defluorination. In contrast, 7-[¹⁸F]­FTrp demonstrated a high in vivo stability and enabled a clear delineation of serotonergic areas and melatonin-producing pineal gland in rat brains. Moreover 7-[¹⁸F]­FTrp accumulated in different tumor xenografts in a chick embryo CAM model. Thus, 7-[¹⁸F]­FTrp 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_i values with selected putaminal MRSI data given for all PINK1 mutation carriers (n = 11) and for individuals with heterozygous mutations only (n = 9).

<p>r = Spearman rank correlation coefficient; n.s. = not significant.</p

¹H MRSI data of the PINK1 study cohort compared to age-matched healthy controls.

<p>Data are given as mean (1SD). 95% CI = 95% confidence interval.</p

³¹P MRSI data of the PINK1 study cohort compared to age-matched healthy controls.

<p>Data are given as mean (1SD). 95% CI = 95% 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 (n = 9, open circles) or two homozygous PINK1 mutations (n = 2, black triangles), the mean putaminal FDOPA K_i values (min⁻¹) determined by PET correlated positively with MRSI-measured MI levels (r = 0.879, p<0.001) (a), but inversely with ATP (r = −0.784, p = 0.008) (b) and GPC concentrations (r = −0.651, p = 0.030) (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% CI = 95% confidence interval. Bold data with an asterisk mark values outside of the 2SD range of controls.</p