“On Water” Direct C‑3 Arylation of 2<i>H</i>‑Pyrazolo[3,4‑<i>b</i>]pyridines

An “on water” palladium-catalyzed direct (hetero)­arylation of 2<i>H</i>-pyrazolo­[3,4-<i>b</i>]­pyridines has been developed. The reactions proceeds smoothly with at low catalytic loading at low temperature providing the C3 (hetero)­arylated products in good to excellent isolated yields. Free <i>NH</i> 3-arylated 7-azaindazoles were also prepared by simple cleavage of the <i>N</i>-protected groups

Isoquinoline-Based Lanthanide Complexes: Bright NIR Optical Probes and Efficient MRI Agents

In the objective of developing ligands that simultaneously satisfy the requirements for MRI contrast agents and near-infrared emitting optical probes that are suitable for imaging, three isoquinoline-based polyaminocarboxylate ligands, <b>L1</b>, <b>L2</b> and <b>L3</b>, have been synthesized and the corresponding Gd³⁺, Nd³⁺ and Yb³⁺ complexes investigated. The specific challenge of the present work was to create NIR emitting agents which (i) have excitation wavelengths compatible with biological applications and (ii) are able to emit a sufficient number of photons to ensure sensitive NIR detection for microscopic imaging. Here we report the first observation of a NIR signal arising from a Ln³⁺ complex in aqueous solution in a microscopy setup. The lanthanide complexes have high thermodynamic stability (log <i>K</i>_LnL =17.7–18.7) and good selectivity for lanthanide ions versus the endogenous cations Zn²⁺, Cu²⁺, and Ca²⁺ thus preventing transmetalation. A variable temperature and pressure ¹⁷O NMR study combined with nuclear magnetic relaxation dispersion measurements yielded the microscopic parameters characterizing water exchange and rotation. Bishydration of the lanthanide cation in the complexes, an important advantage to obtain high relaxivity for the Gd³⁺ chelates, has been demonstrated by ¹⁷O chemical shifts for the Gd³⁺ complexes and by luminescence lifetime measurements for the Yb³⁺ analogues. The water exchange on the three Gd³⁺ complexes is considerably faster (<i>k</i>_ex²⁹⁸ = (13.9–15.4) × 10⁶ s^–1) than on commercial Gd³⁺-based contrast agents and proceeds <i>via</i> a dissociative mechanism, as evidenced by the large positive activation volumes for Gd<b>L1</b> and Gd<b>L2</b> (+10.3 ± 0.9 and +10.6 ± 0.9 cm³ mol^–1, respectively). The relaxivity of Gd<b>L1</b> is doubled at 40 MHz and 298 K in fetal bovine serum (<i>r</i>₁ = 16.1 vs 8.5 mM^–1 s^–1 in HEPES buffer), due to hydrophobic interactions between the chelate and serum proteins. The isoquinoline core allows for the optimization of the optical properties of the luminescent lanthanide complexes in comparison to the pyridinic analogues and provides significant shifts of the excitation energies toward lower values which therefore become more adapted for biological applications. <b>L2</b> and <b>L3</b> bear two methoxy substituents on the aromatic core in ortho and para positions, respectively, that further modulate their electronic structure. The Nd³⁺ and Yb³⁺ complexes of the ligand <b>L3</b>, which incorporates the <i>p</i>-dimethoxyisoquinoline moiety, can be excited up to 420 nm. This wavelength is shifted over 100 nm toward lower energy in comparison to the pyridine-based analogue. The luminescence quantum yields of the Nd³⁺ (0.013–0.016%) and Yb³⁺ chelates (0.028–0.040%) are in the range of the best nonhydrated complexes, despite the presence of two inner sphere water molecules. More importantly, the 980 nm NIR emission band of Yb<b>L3</b> was detected with a good sensitivity in a proof of concept microscopy experiment at a concentration of 10 μM in fetal bovine serum. Our results demonstrate that even bishydrated NIR lanthanide complexes can emit a sufficient number of photons to ensure sensitive detection in practical applications. In particular, these ligands containing an aromatic core with coordinating pyridine nitrogen can be easily modified to tune the optical properties of the NIR luminescent lanthanide complexes while retaining good complex stability and MRI characteristics for the Gd³⁺ analogues. They constitute a highly versatile platform for the development of bimodal MR and optical imaging probes based on a simple mixture of Gd³⁺ and Yb³⁺/Nd³⁺ complexes using an identical chelator. Given the presence of two inner sphere water molecules, important for MRI applications of the corresponding Gd³⁺ analogues, this result is particularly exciting and opens wide perspectives not only for NIR imaging based on Ln³⁺ ions but also for the design of combined NIR optical and MRI probes

Rational Design, Pharmacomodulation, and Synthesis of Dual 5‑Hydroxytryptamine 7 (5-HT₇)/5-Hydroxytryptamine 2A (5-HT_2A) Receptor Antagonists and Evaluation by [¹⁸F]-PET Imaging in a Primate Brain

We report the synthesis of 46 tertiary amine-bearing <i>N</i>-alkylated benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-ones, imidazo­[4,5-<i>b</i>]­pyridin-2­(3<i>H</i>)-ones, imidazo­[4,5-<i>c</i>]­pyridin-2­(3<i>H</i>)-ones, benzo­[<i>d</i>]­oxazol-2­(3<i>H</i>)-ones, oxazolo­[4,5-<i>b</i>]­pyridin-2­(3<i>H</i>)-ones and <i>N</i>,<i>N</i>′-dialkylated benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-ones. These compounds were evaluated against 5-HT₇R, 5-HT_2AR, 5-HT_1AR, and 5-HT₆R as potent dual 5-HT₇/5-HT_2A serotonin receptors ligands. A thorough study of the structure–activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)­piperidin-1-yl)­butyl)-1<i>H</i>-benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-one (<b>79</b>) and 1-(6-(4-(4-fluorobenzoyl)­piperidin-1-yl)­hexyl)-1<i>H</i>-benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-one (<b>81</b>) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, <i>K</i>_B = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, <i>K</i>_B = 0.6 and 16 nM, respectively) signaling pathways of 5-HT₇R and 5-HT_2AR. Both antagonists crossed the blood–brain barrier as evaluated with [¹⁸F] radiolabeled compounds <b>[</b>^<b>18</b><b>F]­79</b> and <b>[</b>^<b>18</b><b>F]­81</b> in a primate’s central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT₇R and 5-HT_2AR in the CNS

PiB-Conjugated, Metal-Based Imaging Probes: Multimodal Approaches for the Visualization of β‑Amyloid Plaques

In an effort toward the visualization of β-amyloid plaques by in vivo imaging techniques, we have conjugated an optimized derivative of the Pittsburgh compound B (PiB), a well-established marker of Aβ plaques, to DO3A-monoamide that is capable of forming stable, noncharged complexes with different trivalent metal ions including Gd³⁺ for MRI and ¹¹¹In³⁺ for SPECT applications. Proton relaxivity measurements evidenced binding of Gd­(DO3A-PiB) to the amyloid peptide Aβ_1–40 and to human serum albumin, resulting in a two- and four-fold relaxivity increase, respectively. Ex vivo immunohistochemical studies showed that the DO3A-PiB complexes selectively target Aβ plaques on Alzheimer’s disease human brain tissue. Ex vivo biodistribution data obtained for the ¹¹¹In-analogue pointed to a moderate blood–brain barrier (BBB) penetration in adult male Swiss mice (without amyloid deposits) with 0.36% ID/g in the cortex at 2 min postinjection