Preclinical evaluation of MC1R targeting theranostic pair [Tb]Tb-crown-αMSH and [Tb]Tb-crown-αMSH.

Background: Targeted radionuclide therapy is established as a highly effective strategy for the treatment of metastatic tumors; however, the co-development of suitable imaging companions to therapy remains significant challenge. Theranostic isotopes of terbium (Tb, Tb, Tb, Tb) have the potential to provide chemically identical radionuclidic pairs, which collectively encompass all modes of nuclear decay relevant to nuclear medicine. Herein, we report the first radiochemistry and preclinical studies involving Tb- and Tb-labeled crown-αMSH, a small peptide-based bioconjugate suitable for targeting melanoma.

Development and application of decatungstate catalyzed C-H F- and F-fluorination, fluoroalkylation and beyond.

Over the past few decades, photocatalytic C-H functionalization reactions have received increasing attention due to the often mild reaction conditions and complementary selectivities to conventional functionalization processes. Now, photocatalytic C-H functionalization is a widely employed tool, supporting activities ranging from complex molecule synthesis to late-stage structure-activity relationship studies. In this perspective, we will discuss our efforts in developing a photocatalytic decatungstate catalyzed C-H fluorination reaction as well as its practical application realized through collaborations with industry partners at Hoffmann-La Roche and Merck, and extension to radiofluorination with radiopharmaceutical chemists and imaging experts at TRIUMF and the BC Cancer Agency.

Tf O-Catalyzed Tandem Cyclization/Trifluoromethylselenolation of Alkynes for Synthesis of CF Se-Containing Heterocycles.

Herein, the tandem synthesis of various CF Se-containing heterocyclic compounds has been developed, using Tf O as the catalyst and trifluoromethyl selenoxides as the electrophilic trifluoromethylselenolation reagents. This process is characterized by its mild conditions, ease of operation, and good functional group compatibility. A variety of alkynes could be transferred into CF Se-containing indoles, benzofurans, benzothiophenes, isoquinolines and chromenes in good yields.

Lewis Acid Promoted Vicinal Oxytrifluoromethylselenolation of Alkenes.

Herein, we have developed a metal-free, Lewis acid promoted vicinal oxytrifluoromethylselenolation of alkenes using trifluoromethyl selenoxides as electrophilic trifluoromethylselenolation reagents and alcohols as nucleophiles. With less steric and good nucleophilic solvents (such as ethanol and methol), TfO-catalyzed oxytrifluoromethylselenolation could be realized, while stoichiometric TfO was required to promote full transformation with less nucleophilic and steric solvents (such as isopropanol and -butanol). The reaction featured good substrate scope, functional group compatibility, and diastereoselectivity.

Preclinical Evaluation of [Tb]Tb-Crown-TATE-A Novel SPECT Imaging Theranostic Agent Targeting Neuroendocrine Tumours.

Terbium radioisotopes (Tb, Tb, Tb, Tb) offer a unique class of radionuclides which encompass all four medicinally relevant nuclear decay modalities (α, , γ, /e), and show high potential for the development of element-matched theranostic radiopharmaceuticals. The goal of this study was to design, synthesise, and evaluate the suitability of crown-TATE as a new peptide-conjugate for radiolabelling of [Tb]Tb and [Tb]Tb, and to assess the imaging and pharmacokinetic properties of each radiotracer in tumour-bearing mice. [Tb]Tb-crown-TATE and [Tb]Tb-crown-TATE were prepared efficiently under mild conditions, and exhibited excellent stability in human serum (>99.

Visible-Light-Induced Monofluoroalkenylation and -Difluoroallylation of Inactivated C(sp)-H Bonds via 1,5-Hydrogen Atom Transfer (HAT).

The direct monofluoroalkenylation of C(sp)-H bonds is of great importance and quite challenging. Current methods have been restricted to the monofluoroalkenylation of activated C(sp)-H bonds. Here, we reported the photocatalyzed C(sp)-H monofluoroalkenylation of inactivated C(sp)-H bonds with -difluoroalkenes via 1,5-hydrogen atom transfer.

[3+2] Cycloaddition of alkyl aldehydes and alkynes enabled by photoinduced hydrogen atom transfer.

[3+2] Cycloaddition is a step- and atom-economic method for the synthesis of five-membered rings. Despite the great success of 1,3-dipolar cycloadditions, the radical [3+2] annulation of alkynes remains a formidable challenge. Herein, a photoinduced decatungstate-catalyzed [3+2] cycloaddition of various internal alkynes using abundant aliphatic aldehydes as a three-carbon synthon is developed, producing elaborate cyclopentanones in 100% atom economy with excellent site-, regio-, and diastereoselectivity under mild conditions.

Oxalates as Activating Groups for Tertiary Alcohols in Photoredox-Catalyzed -Difluoroallylation To Construct All-Carbon Quaternary Centers.

Construction of challenging and important all-carbon quaternary centers has received growing attention. Herein, with oxalates as activating groups for tertiary alcohols, we report photoredox-catalyzed -difluoroallylation to construct all-carbon quaternary centers enabled by efficient tertiary radical addition to α-trifluoromethyl alkenes. This transformation shows good functional group tolerance for both α-trifluoromethyl alkenes and oxalates.

Trifluoromethyl Selenoxides: Electrophilic Reagents for C-H Trifluoromethylselenolation of (Hetero)Arene.

The trifluoromethylselenyl group (CFSe) has become an emerging fluorinated moiety in synthetic chemistry due to its high Hansch lipophilicity parameter and strong electron-withdrawing effect. The trifluoromethylselenolation is hampered by limited synthetic methods and related reagents. Herein, we designed and synthesized the new electrophilic trifluoromethylselenolation reagents, trifluoromethyl selenoxides, which are easy to prepare and easy-to-handle and are not moisture or air sensitive.

Recent advances in difunctionalization of alkenes using pyridinium salts as radical precursors.

In this review, we summarise the recent applications of pyridinium salts in the radical-mediated difunctionalization of alkenes. Pyridinium salts are a privileged class of compounds that show great utility in natural products and synthetic chemistry. Various organic transformations of pyridinium salts, especially in radical chemistry, have been developed in recent years.

Decatungstate Catalyzed Synthesis of Trifluoromethylthioesters from Aldehydes via a Radical Process.

Here we report a mild and general method for the trifluoromethylthiolation of aldehydes using -trifluoromethylthiosaccharin as the CFS radical source and sodium decatungstate (NaDT) as the photocatalyst. This reaction proceeds via hydrogen atom abstraction by photoactivated DT and features good functional groups and substrate tolerance. Generally, electron-rich aldehydes demonstrate better reactivity than electron-deficient ones and good selectivity is observed for the trifluoromethylthiolation of aldehydic C-H bonds over tertiary and benzylic C-H bonds.

Radical Chain Isomerization of -Sulfonyl Ynamides to Ketenimines and Its Application to Furan Dearomatization.

A radical chain isomerization of -sulfonyl ynamides to isolable ketenimines is developed, featuring mild reaction conditions, a high efficiency, ∼100% atom economy, a broad substrate scope, and column chromatography-free workup in most cases. Meanwhile, an unprecedented dearomatization of furans is achieved by the radical chain isomerization-triggered aza-Claisen rearrangement, providing highly chemo-, regio-, stereo-, and diastereoselective access to functionalized quaternary nitriles.

Synthesis of DOTA-pyridine chelates for Cu coordination and radiolabeling of αMSH peptide.

Background: Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x = 1-4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone.

Internal Alkyne-Directed Fluorination of Unactivated C(sp)-H Bonds.

A silver-mediated internal alkyne-guided fluorination of unactivated C(sp)-H bonds is described. The reaction provides a facile access to γ-fluorinated fluoroalkylated ()-alkenes from readily available alkynes in promising yields with excellent regioselectivity, stereoselectivity, and site selectivity.

Synthesis and Evaluation of a Macrocyclic Actinium-225 Chelator, Quality Control and In Vivo Evaluation of Ac-crown-αMSH Peptide.

Targeted alpha-therapy (TAT) has great potential for treating a broad range of late-stage cancers by delivering a focused and lethal radiation dose to tumors. Actinium-225 ( Ac) is an emerging alpha emitter suitable for TAT; however, the availability of chelators for Ac remains limited to a small number of examples (DOTA and macropa). Herein, we report a new Ac macrocyclic chelator named 'crown', which binds quantitatively and rapidly (<10 min) to Ac at ambient temperature.

Site-Selective, Late-Stage C-H F-Fluorination on Unprotected Peptides for Positron Emission Tomography Imaging.

Peptides are often ideal ligands for diagnostic molecular imaging due to their ease of synthesis and tuneable targeting properties. However, labelling unmodified peptides with F for positron emission tomography (PET) imaging presents a number of challenges. Here we show the combination of photoactivated sodium decatungstate and [ F]-N-fluorobenzenesulfonimide effects site-selective F-fluorination at the branched position in leucine residues in unprotected and unaltered peptides.

Direct heterobenzylic fluorination, difluorination and trifluoromethylthiolation with dibenzenesulfonamide derivatives.

Functionalization of heterocyclic scaffolds with mono- or difluoroalkyl groups provides unique opportunities to modulate drug p, influence potency and membrane permeability, and attenuate metabolism. While advances in the addition of fluoroalkyl radicals to heterocycles have been made, direct C(sp)-H heterobenzylic fluorination is comparatively unexplored. Here we demonstrate both mono- and difluorination of a range of alkyl heterocycles using a convenient process that relies on transient sulfonylation by the electrophilic fluorinating agent -fluorobenzenesulfonimide.

F-Fluorination of Unactivated C-H Bonds in Branched Aliphatic Amino Acids: Direct Synthesis of Oncological Positron Emission Tomography Imaging Agents.

A mild and selective photocatalytic C-H F-fluorination reaction has been developed that provides direct access to F-fluorinated amino acids. The biodistribution and uptake of three F-labeled leucine analogues via LAT1 mediated transport in several cancer cell lines is reported. Positron emission tomography imaging of mice bearing PC3 (prostate) or U87 (glioma) xenografts using 5-[F]-fluorohomoleucine showed high tumor uptake and excellent tumor visualization, highlighting the utility of this strategy for rapid tracer discovery for oncology.

Efficient Pathway for the Preparation of Aryl(isoquinoline)iodonium(III) Salts and Synthesis of Radiofluorinated Isoquinolines.

Iodonium compounds play a pivotal role in (18) F-fluorination of radiopharmaceuticals containing non-activated arenes. However, preparation of these species is limited to oxidation conditions or exchange with organometallics that are prepared from aryl halides. Herein we describe a novel "one-pot" process to assemble aryl(isoquinoline)iodonium salts in 40-94 % yields from mesoionic carbene silver complex and Aryl-I-Py2 (OTf)2 .

Highly selective Pd-catalyzed intermolecular fluorosulfonylation of styrenes.

A novel Pd-catalyzed intermolecular regio- and diastereoselective fluorosulfonylation of styrenes has been developed under mild conditions. This reaction exhibits a wide range of functional-group tolerance in styrenes and arylsulfinic acids to afford various β-fluoro sulfones. Preliminary mechanistic study reveals an unusual mechanism, in which a high-valent L2Pd(III)F species side-selectively reacts with a benzylic carbon radical to deliver a C-F bond.

Synthesis of multisubstituted enamides via Pd-catalyzed chloroallylation of ynamides.

An atom-economic approach to the regio- and stereoselective assembly of highly substituted enamides is described via the Pd-catalyzed chloroallylation of ynamides at room temperature, which offers a simple and practical alternative to the stereodefined multisubstituted enamides.

Palladium-catalyzed haloallylation of aromatic ynol ethers with allyl chlorides: a highly regio- and stereoselective approach to (1E)-α-chloroenol ethers.

Described herein is a Pd-catalyzed haloallylation of aromatic ynol ethers and allyl chlorides, allowing facile access to (1E)-α-chloroenol ethers in a highly regio- and stereoselective manner. The synthetic utility of this method is demonstrated well by the synthesis of the stereodefined multisubstituted enol ethers and α-allylated carbonyl compounds.

Synthesis of cis-1,2-dihaloalkenes featuring palladium-catalyzed coupling of haloalkynes and α,β-unsaturated carbonyls.

A highly regio- and stereoselective method for the synthesis of cis-1,2-dihaloalkenes through Pd-catalyzed coupling of haloalkynes and α,β-unsaturated carbonyls has been reported. Excellent stereoselectivities (Z/E up to >98:2) were observed in most cases. This method was subsequently applied to synthesize the functionalized conjugated enyne via the mono-Sonogashira coupling reaction of cis-1-chloro-2-iodoalkene.