A General Copper‐Mediated Nucleophilic 18 F Fluorination of Arenes

Lau

Journal of Enzyme Inhibition and Medicinal Chemistry

et al. 2017

Carbonic anhydrase IX (CA-IX) is a marker for tumor hypoxia, and its expression is negatively correlated with patient survival. CA-IX represents a potential target for eliminating hypoxic cancers. We synthesized fluorinated cationic sulfonamide inhibitors 1-3 designed to target CA-IX. The binding affinity for CA-IX ranged from 0.22 to 0.96 lM. We evaluated compound 2 as a diagnostic PET imaging agent. Compound 2 was radiolabeled with 18 F in 10 ± 4% decay-corrected radiochemical yield with 85.1 ± 70.3 GBq/lmol specific activity and >98% radiochemical purity.18 F-labeled 2 was stable in mouse plasma at 37 C after 1 h incubation. PET/CT imaging was conducted at 1 h post-injection in a human colorectal cancer xenograft model.18 F-labeled 2 cleared through hepatobiliary and renal pathways. Tumor uptake was approximately 0.41 ± 0.06% ID/g, with a tumor-to-muscle ratio of 1.99 ± 0.25. Subsequently, tumor xenografts were visualized with moderate contrast. This study demonstrates the use of a cationic motif for conferring isoform selectively for CA-IX imaging agents. ARTICLE HISTORY

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Design, synthesis and evaluation of¹⁸F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging

Lau

Journal of Enzyme Inhibition and Medicinal Chemistry

et al. 2017

Labelled Comp Radiopharmac

“…Via confocal fluorescence microscopy, the cell internalization of the particles was verified. The cellular uptake of the dually modified particles could partly be blocked by BBN (7)(8)(9)(10)(11)(12)(13)(14). The animal experiments revealed a higher accumulation of 4 in PC3-tumor in comparison to muscle at 24 h post i.v.…”

Section: Resultsmentioning

confidence: 99%

“…While typically these isotopes are obtained from generators or are produced on a small cyclotron using a solid target and a solid-target station, these production methods can affect the availability or selection of radiometal due to the expense or inability to produce the isotope of choice. Liquid targets, on the other hand, are ubiquitous and can provide an alternative and inexpensive method to produce radiometal isotopes for research quantities, or even clinical quantities, with the ability to switch between the productions of different metals in a short amount of time [4][5][6][7][8]. Methods At TRIUMF, Vancouver Canada, we have used this approach, to develop a dedicated liquid target system for the production of technetium94m [6], scandium-44 [7], and gallium-68, yttrium-86, zirconium-89, copper-61 [8].…”

Section: Objectivesmentioning

confidence: 99%

“…Liquid targets, on the other hand, are ubiquitous and can provide an alternative and inexpensive method to produce radiometal isotopes for research quantities, or even clinical quantities, with the ability to switch between the productions of different metals in a short amount of time [4][5][6][7][8]. Methods At TRIUMF, Vancouver Canada, we have used this approach, to develop a dedicated liquid target system for the production of technetium94m [6], scandium-44 [7], and gallium-68, yttrium-86, zirconium-89, copper-61 [8]. In all cases except of technetium-94m, a nitrate solution (calcium nitrate, zinc nitrate, zirconium nitrate, and strontium nitrate) as starting metal was prepared.…”

Section: Objectivesmentioning

confidence: 99%

See 1 more Smart Citation

Poster Presentations

2017

C o n t e n t s P o s t e r RAPID FIRE POSTER SESSION I P 001 Preliminary biological evaluation of Re(CO)3Helmholtz-Zentrum Institute of Radiopharmaceutical Cancer Research, Neuroradiopharmaceuticals, Leipzig, Germany; 2 Helmholtz-Zentrum Institute of Radiopharmaceutical Cancer Research, Radiopharmaceutical and Chemical Biology, Germany; 3 DanPET AB, Malmö, Sweden P 017 [ Aix-Marseille University, CNRS, LP3 UMR 7341, Campus de Luminy, Marseille Cedex 9, France; 3 3P.N. Lebedev Physical Institute of RAS, Moscow, RussiaPoster: S1 22nd International Symposium on Radiopharmaceutical Sciences J Label Compd Radiopharm 2017: 60 (Suppl. 1): S111 S640 - Research & development, Korea Republic (South); 2 Chonbuk National University Medical School and Hospital, Department of Nuclear Medicine, Korea Republic (South); 3 Chonbuk National University Medical School and Hospital, Molecular Imaging & Therapeutic Medicine Research Center, Jeonju-si, Korea Republic ( F]FEDA) was prepared by the nucleophilic 18 F-fluorination of its tosyl precursor. The labeled compound was isolated by HPLC and formulated in a 0.05 M TEAP solution containing 10% ethanol. Structure of 18 F-tracer was assigned using X-ray structural data for its nonradioactive Re(CO)3(FEDA) standard. Preliminary PET imaging studies were performed using Inveon micro-PET/CT system (Siemens) on normal Sprague-Dawley rats. Regions of interest (ROI) and time activity-curves (TACs) were derived for the subsequent data analysis and to assess principle pharmacokinetics in vivo. Results Re(CO)3([ 18 F]FEDA) was efficiently obtained as a single species with high radiochemical purity (>99%). Dynamic PET imaging showed a rapid clearance of the 18 F-tracer from the blood and from most other tissues and organs (Fig. 1). It also revealed the tracer's rapid renal extraction and high specificity for renal excretion. In addition, PET/CT scans did not show any bone uptake verifying the absence of free [ Table 1) were explored. Sulfonyl fluorides (B) were synthesized from the corresponding sulfonyl chloride (A) (50 µg) in acetonitrile (50 µL) and fluoride in water (50 µL) in the presence of 10 × PBS (5 µL). The radiochemical yield was determined by radio-TLC, and the amount of sulfonyl fluoride was determined by radio-HPLC. Both measurements were used to calculate SA of sulfonyl fluoride, which was then converted to the SA of fluoride. Results Fluorine-18 sulfonyl fluorides were formed exclusively as the radioactive products in over 90% yields under the conditions in Table 1. The UV peak of B was well separated from that of the precursor A, allowing the measurement of UV mass without further purification. Ga. Methods Equilibrium properties of A and B and its complexes were studied by pH-potentiometry, UV-VIS spectrophotometry, 1 H-and 71 Ga-NMR spectroscopy. Kinetic inertness of Ga-A and Ga-B was studied via exchange reaction with Cu 2+ -ion as well as ligand exchange between Ga-A /Ga-B and transferrin. The influence of different metal...

Transition‐Metal‐Mediated and Transition‐Metal‐Catalyzed Carbon–Fluorine Bond Formation

Neumann

Ritter

2020

Organic Reactions

The number and diversity of methods for installing carbon–fluorine bonds have substantially expanded over the past two decades, enabling enantioselective fluorinations, reactions with complex substrates, and the use of ever simpler reaction precursors. Fluorination chemistry was long held back by unreactive alkali fluoride salts and highly reactive electrophilic fluorine sources, such as molecular fluorine and cobalt(III) fluoride. The introduction of fluorination reagents with controlled reactivity has been a key driving force in harnessing the reactivity of fluoride, as has the strategic use of transition metals. These approaches enable predictable and functional‐group‐tolerant carbon–fluorine bond formation. Herein, transition‐metal‐catalyzed and transition‐metal‐mediated syntheses of aromatic, heteroaromatic, and alkyl fluorides are reviewed. In addition, methods for allylic fluorination, benzylic fluorination, and fluorination α to carbonyl groups are presented. The influence of these reactions on the synthesis of complex fluorinated molecules and the preparation of 18 F‐PET probes are described, and experimental procedures for illustrative examples are included.