11CO2 Fixation: A Renaissance in PET Radiochemistry

Carbon-11 labelled carbon dioxide is the cyclotron-generated feedstock reagent for most positron emission tomography (PET) tracers using this radionuclide. Most carbon-11 labels, however, are installed using derivative reagents generated from [11C]CO2. In recent years, [11C]CO2 has seen a revival in applications for the direct incorporation of carbon-11 into functional groups such as ureas, carbamates, oxazolidinones, carboxylic acids, esters, and amides. This review summarizes classical [11C]CO2 fixation strategies using organometallic reagents and then focuses on newly developed methods that employ strong organic bases to reversibly capture [11C]CO2 into solution, thereby enabling highly functionalized labelled compounds to be prepared. Labelled compounds and radiopharmaceuticals that have been translated to the clinic are highlighted.Chemistry and Chemical Biolog

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals-radiosynthesis and ex vivo biodistribution of [18F] 3-(4-(2-(2-(2-fluoroethoxy) ethoxy) ethylthio)-1, 2, 5-thiadiazol-3-yl)-1-methyl-1, 2, 5, 6-tetrahydropyridine

Muscarinic receptors have been implicated in neurological disorders including Alzheimer’s disease, Parkinson’s disease, and schizophrenia. Nineteen derivatives of thiadiazolyltetrahydropyridine (TZTP), a core that has previously shown high affinities towards muscarinic receptor subtypes, were synthesized and evaluated via in vitro binding assays. The title compound, a fluoro-polyethyleneglycol analog of TZTP (4c), was subsequently labelled with fluorine-18. Fluorine-18-labelled 4c was produced, via an automated synthesis, in an average radiochemical yield of 36% (uncorrected for decay), with high radiochemical purity (>99%) and high specific activity (326 GBq/µmol; end-of-bombardment), within 40 min (n = 3). Ex vivo biodistribution studies following tail-vein injection of [18F]4c in conscious rats displayed sufficient brain uptake (0.4%–0.7% injected dose / gram of wet tissue in all brain regions at 5 min post injection); however, there were substantial polar metabolites present in the brain, thereby precluding future use of [18F]4c for imaging in the central nervous system.peer-reviewe

Towards a one-pot synthesis of 11C-amides via copper(I) catalyzed [11C]CO2 fixation

Synthesis of 11C-amides have been hindered by the lack of versatile synthetic methods capable of directly and easily converting [11C]CO2 into 11C-amides without conversion of [11C]CO2 into [11C]CO. Herein, we explore an alternative one-pot synthesis of 11C-amides using a metal catalyst via the addition of boronic acids/esters to [11C]isocyanates generated in situ from primary amines and [11C]CO2. A proof-of-concept for synthesizing [11C]benzanilide directly from [11C]CO2 using organoboronic esters and tributylphosphoranylidines using copper(I) catalysis was demonstrated. We successfully utilized this novel method for the radiosynthesis of [11C]benzanilide, in RCC of 12%. Further development of this methodology will be needed for wider application in the radiolabeling of 11C PET radiotracers. Identification of catalyst capable of aiding the transmetallation step while not impeding [11C]CO2 fixation are likely needed for wider application of this methodologyThe presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author

(E)-2-(2-Methyl­cyclo­hexyl­idene)hydrazinecarbothio­amide

In the crystal of the title compound, C8H15N3S, mol­ecules are linked by N—H⋯S hydrogen bonds, forming chains along [10]. An intra­molecular N—H⋯N hydrogen bond is also present

Design and Prototype of an Automated Column-Switching HPLC System for Radiometabolite Analysis

Column-switching high performance liquid chromatography (HPLC) is extensively used for the critical analysis of radiolabeled ligands and their metabolites in plasma. However, the lack of streamlined apparatus and consequently varying protocols remain as a challenge among positron emission tomography laboratories. We report here the prototype apparatus and implementation of a fully automated and simplified column-switching procedure to allow for the easy and automated determination of radioligands and their metabolites in up to 5 mL of plasma. The system has been used with conventional UV and coincidence radiation detectors, as well as with a single quadrupole mass spectrometer

Recent applications of a single quadrupole mass spectrometer in 11C, 18F and radiometal chemistry

Mass spectrometry (MS) has longstanding applications in radiochemistry laboratories, stemming from carbon-dating. However, research on the development of radiotracers for molecular imaging with either positron emission tomography (PET) or single photon emission computed tomography has yet to take full advantage of MS. This inertia has been attributed to the relatively low concentrations of radiopharmaceutical formulations and lack of access to the required MS equipment due to the high costs for purchase and maintenance of specialized MS systems. To date, single quadrupole (SQ)-MS coupled to liquid chromatography (LC) systems is the main form of MS that has been used in radiochemistry laboratories. These LC–MS systems are primarily used for assessing the chemical purity of radiolabeling precursor or standard molecules but also have applications in the determination of metabolites. Herein, we highlight personal experiences using a compact SQ-MS in our PET radiochemistry laboratories, to monitor the small amounts of carrier observed in most radiotracer preparations, even at high molar activities. The use of a SQ-MS in the observation of the low mass associated with non-radioactive species which are formed along with the radiotracer from the trace amounts of carrier found is demonstrated. Herein, we describe a pre-concentration system to detect dilute radiopharmaceutical formulations and metabolite analyses by SQ-MS. Selected examples where SQ-MS was critical for optimization of radiochemical reactions and for unequivocal characterization of radiotracers are showcased. We also illustrate examples where SQ-MS can be applied in identification of radiometal complexes and development of a new purification methodology for Pd-catalyzed radiofluorination reactions, shedding light on the identity of metal complexes present in the labelling solution

Chelate-free metal ion binding and heat-induced radiolabeling of iron oxide nanoparticles† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c4sc02778g Click here for additional data file.

A novel reaction for chelate-free, heat-induced metal ion binding and radiolabeling of ultra-small paramagnetic iron oxide nanoparticles (USPIOs) has been established. Radiochemical and non-radioactive labeling studies demonstrated that the reaction has a wide chemical scope and is applicable to p-, d- and f-block metal ions with varying ionic sizes and formal oxidation states from 2+ to 4+. Radiolabeling studies found that 89Zr–Feraheme (89Zr–FH or 89Zr–ferumoxytol) can be isolated in 93 ± 3% radiochemical yield (RCY) and >98% radiochemical purity using size-exclusion chromatography. 89Zr–FH was found to be thermodynamically and kinetically stable in vitro using a series of ligand challenge and plasma stability tests, and in vivo using PET/CT imaging and biodistribution studies in mice. Remarkably, ICP-MS and radiochemistry experiments showed that the same reaction conditions used to produce 89Zr–FH can be employed with different radionuclides to yield 64Cu–FH (66 ± 6% RCY) and 111In–FH (91 ± 2% RCY). Electron magnetic resonance studies support a mechanism of binding involving metal ion association with the surface of the magnetite crystal core. Collectively, these data suggest that chelate-free labeling methods can be employed to facilitate clinical translation of a new class of multimodality PET/MRI radiotracers derived from metal-based nanoparticles. Further, this discovery is likely to have broader implications in drug delivery, metal separation science, ecotoxicology of nanoparticles and beyond

N-Isopropyl­benzamide

In the title compound, C10H13NO, the dihedral angle between the amide group and the phenyl ring is 30.0 (3)°. In the crystal structure, inter­molecular N—H⋯O hydrogen bonds link mol­ecules into one-dimensional chains along the a axis

Structure-based optimization and binding assays for discovery of tau PET radiotracers: Synthesis and in vivo evaluation of [11C]Z-3272

Human tau protein has six isoforms, differing in the number of microtubule-binding repeats. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are primarily 4-repeat (4R)-tauopathies, and Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE) are mixed 3R/4R-tau. Here, a promising lead compound for positron emission tomography (PET) imaging of non-AD tauopathies (Z5873993272; (methyl-1-(5-(7-hydroxynaphthalen-2-yl)pyridin-2-yl)piperidine-4-carboxylate; Z-3272), was identified as a potential 4R-tau binding ligand through computational structure-based optimization from the 2D structure of known 4R-tau ligands, followed by iterative competition binding assays. Homologous binding assays in post-mortem AD, PSP, and CBD brain with [3H]Z-3272 provided Kd (nM) values (n = 3) of AD = 1.2 ± 0.1, PSP = 2.7 ± 0.9, and CBD = 1.7 ± 0.1. [11C]Z-3272 was synthesized by 11C-methylation, by reaction of [11C]CH3I with 1-(5-(7-hydroxynaphthalen-2-yl)pyridin-2-yl)piperidine-4-carboxylic acid with NaHCO3 in DMF at 70 ºC for 3 min. The crude product was purified by semi-preparative HPLC and formulated in saline, with an overall synthesis time of 35 min from end of bombardment. [11C]Z-3272 was isolated with a non-decay corrected radiochemical yield of 4 ± 1% (n = 4), high radiochemical purity (>95%), and high molar activity (149 ± 55.5 GBq/μmol). PET imaging following bolus injection of [11C]Z-3272 in rats showed high initial brain radioactivity (>2.3 standardized uptake values (SUV)) with moderate washout (~0.7 SUV at 60 min), however, ex vivo studies revealed the rapid formation of troublesome brain penetrant radiometabolites. Medicinal chemistry optimization is underway to improve binding affinity, selectivity, and metabolic stability.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author