Pyridine-based strategies towards nitrogen isotope exchange and multiple isotope incorporation.

Isotopic labeling is at the core of health and life science applications such as nuclear imaging, metabolomics and plays a central role in drug development. The rapid access to isotopically labeled organic molecules is a sine qua non condition to support these societally vital areas of research. Based on a rationally driven approach, this study presents an innovative solution to access labeled pyridines by a nitrogen isotope exchange reaction based on a Zincke activation strategy. The technology conceptualizes an opportunity in the field of isotope labeling. 15N-labeling of pyridines and other relevant heterocycles such as pyrimidines and isoquinolines showcases on a large set of derivatives, including pharmaceuticals. Finally, we explore a nitrogen-to-carbon exchange strategy in order to access 13C-labeled phenyl derivatives and deuterium labeling of mono-substituted benzene from pyridine-2H5. These results open alternative avenues for multiple isotope labeling on aromatic cores.

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds.

The presence of positron emission tomography (PET) centers at most major hospitals worldwide, along with the improvement of PET scanner sensitivity and the introduction of total body PET systems, has increased the interest in the PET tracer development using the short-lived radionuclides carbon-11. In the last few decades, methodological improvements and fully automated modules have allowed the development of carbon-11 tracers for clinical use. Radiolabeling natural compounds with carbon-11 by substituting one of the backbone carbons with the radionuclide has provided important information on the biochemistry of the authentic compounds and increased the understanding of their in vivo behavior in healthy and diseased states. The number of endogenous and natural compounds essential for human life is staggering, ranging from simple alcohols to vitamins and peptides. This review collates all the carbon-11 radiolabeled endogenous and natural exogenous compounds synthesised to date, including essential information on their radiochemistry methodologies and preclinical and clinical studies in healthy subjects.

Synthesis and Assessment of Novel Probes for Imaging Tau Pathology in Transgenic Mouse and Rat Models.

Aggregated tau protein is a core pathology present in several neurodegenerative diseases. Therefore, the development and application of positron emission tomography (PET) imaging radiotracers that selectively bind to aggregated tau in fibril form is of importance in furthering the understanding of these disorders. While radiotracers used in human PET studies offer invaluable insight, radiotracers that are also capable of visualizing tau fibrils in animal models are important tools for translational research into these diseases. Herein, we report the synthesis and characterization of a novel library of compounds based on the phenyl/pyridinylbutadienylbenzothiazoles/benzothiazolium (PBB3) backbone developed for this application. From this library, we selected the compound LM229, which binds to recombinant tau fibrils with high affinity (Kd = 3.6 nM) and detects with high specificity (a) pathological 4R tau aggregates in living cultured neurons and mouse brain sections from transgenic human P301S tau mice, (b) truncated human 151-351 3R (SHR24) and 4R (SHR72) tau aggregates in transgenic rat brain sections, and (c) tau neurofibrillary tangles in brain sections from Alzheimer's disease (3R/4R tau) and progressive supranuclear palsy (4R tau). With LM229 also shown to cross the blood-brain barrier in vivo and its effective radiolabeling with the radioisotope carbon-11, we have established a novel platform for PET translational studies using rodent transgenic tau models.

Ammonium [11C]thiocyanate: revised preparation and reactivity studies of a versatile nucleophile for carbon-11 radiolabelling.

Herein we report the preparation of ammonium [11C]thiocyanate via the reaction of [11C]CS2 with ammonia. The [11C]SCN- ion is demonstrated as a potent nucleophile that can be used to readily generate a range of 11C-labelled thiocyanate molecules in high conversions. Furthermore, novel 11C-labelled thiazolone molecules can be easily prepared from the intermediate α-thiocyanatophenones via an acid mediated cyclisation reaction.

Carbon-11 radiolabelling of organosulfur compounds: (11) C synthesis of the progesterone receptor agonist tanaproget.

Herein a new (11) C radiolabelling strategy for the fast and efficient synthesis of thioureas and related derivatives using the novel synthon, (11) CS2 , is reported. This approach has enabled the facile labelling of a potent progesterone receptor (PR) agonist, [(11) C]Tanaproget, by the intramolecular reaction of the acyclic aminohydroxyl precursor with (11) CS2 , which has potential applications as a positron emission tomography radioligand for cancer imaging.

Evaluation of 11C-BU99008, a PET ligand for the imidazoline2 binding sites in rhesus brain.

UNLABELLED: The development of a PET radioligand selective for I2-imidazoline binding sites (I2BS) would enable, for the first time, specific, measurable in vivo imaging of this target protein, along with assessment of alterations in expression patterns of this protein in disease pathophysiology. METHODS: BU99008 was identified as the most promising I2BS radioligand candidate and radiolabeled with (11)C via methylation. The in vivo binding properties of (11)C-BU99008 were assessed in rhesus monkeys to determine brain penetration, brain distribution, binding specificity and selectivity (via the use of the unlabeled blockers), and the most appropriate kinetic model for analyzing data generated with this PET radioligand. RESULTS: (11)C-BU99008 was demonstrated to readily enter the brain, resulting in a heterogeneous distribution (globus pallidus > cortical regions > cerebellum) consistent with the reported regional I2BS densities as determined by human tissue section autoradiography and preclinical in vivo PET studies in the pig. In vivo competition studies revealed that (11)C-BU99008 displayed reversible kinetics specific for the I2BS. The multilinear analysis (MA1) model was the most appropriate analysis method for this PET radioligand in this species. The selective I2BS blocker BU224 was shown to cause a saturable, dose-dependent decrease in (11)C-BU99008 binding in all regions of the brain assessed, further demonstrating the heterogeneous distribution of I2BS protein in the rhesus brain and binding specificity for this radioligand. CONCLUSION: These data demonstrate that (11)C-BU99008 represents a specific and selective PET radioligand for imaging and quantifying the I2BS, in vivo, in the rhesus monkey. Further work is under way to translate the use of (11)C-BU99008 to the clinic.

Transition metal mediated [(11) C]carbonylation reactions: recent advances and applications.

[(11) C]Carbon monoxide is undoubtedly a highly versatile radiolabelling synthon with many potential applications for the synthesis of positron emission tomography (PET) tracer molecules and functional groups, but why has it not found more applications in the PET radiolabelling arena? Today, (11) CO radiolabelling is still primarily viewed as a niche area; however, there are signs that this is beginning to change as some of the technical and chemistry challenges of producing, handling and reacting (11) CO are overcome. This mini review covers the more recent developments of (11) CO-labelling chemistry and is focused on palladium and rhodium-mediated carbonylation reactions that are growing in importance and finding wider application for carbon-11 PET radiotracer development.

Palladium-mediated oxidative carbonylation reactions for the synthesis of (11) C-radiolabelled ureas.

Palladium(II)-mediated oxidative carbonylation reactions have been used to synthesize (11) C-radiolabelled ureas via the coupling of amines with [(11) C]carbon monoxide, in a one-pot process. Following trapping of (11) CO in a solution of copper(I) tris(3,5-dimethylpyrazolyl)borate, homocoupling reactions of primary aliphatic amines proceed in the presence of Pd(PPh3 )2 Cl2 to give the corresponding N,N-disubstituted [(11) C]ureas. Secondary amines do not produce the corresponding N,N,N,N-tetrasubsituted [(11) C]ureas under these conditions. This difference in reactivity allows for the formation of unsymmetrical N,N',N'-trisubstituted [(11) C]ureas using a mixture of a primary amine and a reactive secondary amine. The potential use of this method in positron emission tomography (PET) was demonstrated by the synthesis of the M1 muscarinic acetylcholine receptor radiotracer, [(11) C-carbonyl]GSK1034702.

Imaging imidazoline-I2 binding sites in porcine brain using 11C-BU99008.

UNLABELLED: Changes in the density of imidazoline-I(2) binding sites have been observed in a range of neurologic disorders including Alzheimer's disease, Huntington's chorea, and glial tumor; however, the precise function of these sites remains unclear. A PET probe for I(2) binding sites would further our understanding of the target and may find application as a biomarker for early disease diagnosis. Compound BU99008 has previously been identified as a promising I(2) ligand from autoradiography studies, displaying high affinity and good selectivity toward the target. In this study, BU99008 was radiolabeled with (11)C in order to image the I(2) binding sites in vivo using PET. METHODS: (11)C-BU99008 was radiolabeled by N-alkylation of the desmethyl precursor using (11)C-methyl iodide. A series of PET experiments was performed to investigate the binding of (11)C-BU99008 in porcine brains, in the presence or absence of a nonradiolabeled, competing I(2) ligand, BU224. RESULTS: (11)C-BU99008 was obtained in good yield and specific activity. In vivo, (11)C-BU99008 displayed good brain penetration and gave a heterogeneous distribution with high uptake in the thalamus and low uptake in the cortex and cerebellum. (11)C-BU99008 brain kinetics were well described by the 1-tissue-compartment model, which was used to provide estimates for the total volume of distribution (V(T)) across brain regions of interest. Baseline V(T) values were ranked in the following order: thalamus > striatum > hippocampus > frontal cortex ≥ cerebellum, consistent with the known distribution and concentration of I(2) binding sites. Administration of a selective I(2) binding site ligand, BU224, reduced the V(T) to near-homogeneous levels in all brain regions. CONCLUSION: (11)C-BU99008 appears to be a suitable PET radioligand for imaging the I(2) binding sites in vivo.

Hemilabile and reversible carbon monoxide binding properties of iron(II), cobalt(II) and nickel(II) complexes containing a new tridentate P-S-N ligand.

Several first-row transition metal complexes of the formulation [M(1)(2)](X)(2) {where 1 = Ph(2)PCH(2)CH(2)S(2-C(6)H(4)NH(2)); M = Fe(II), X = BF(4)(-) (2); M = Co(II), X = BF(4)(-) (3), Ni(II), X = ClO(4)(-) (4)} have been prepared by reaction of two equivalents of the new P-S-N ligand Ph(2)PCH(2)CH(2)S(2-C(6)H(4)NH(2)) 1 with one equivalent of the appropriate [M(OH(2))(6)](X)(2) precursor in acetonitrile. In the solid state, complexes 2-4 exist as distorted centrosymmetric octahedral structures featuring facially capping ligands in an all-trans arrangement. Reaction of 2 and 3 with a stream of carbon monoxide (1 atm.) for 5 min in acetonitrile generates iron(II) monocarbonyl species of formulation [Fe(CO)(1)(2)](BF(4))(2)2a, and a cobalt(II) dicarbonyl complex, [Co(CO)(2)(1)(2)](BF(4))(2)3a, which can be isolated in the solid state. Complete removal of CO is achieved by either heating to reflux samples of 2a in acetonitrile for 5 min or by heating solid samples of 3a at 120 °C in vacuo over a period of 4 h. The binding of carbon monoxide is fully reversible for 2 and 3 and can be repeated over multiple cycles. When the same trapping reactions were carried out with very low radiochemical (11)CO concentrations, metal carbonyl species were no longer formed. It is likely that the kinetics of (11)CO adduct formation are too slow to allow for effective trapping under the applied radiochemical conditions.

Microfluidic reactions using [11C]carbon monoxide solutions for the synthesis of a positron emission tomography radiotracer.

Microfluidic technology has been used to perform [(11)C]carbonylation reactions using solutions containing [(11)C]CO in the form of the complex, copper(i)tris(3,5-dimethylpyrazolyl)borate-[(11)C]carbonyl (Cu(Tp*)[(11)C]CO). The synthesis of the model compound [(11)C]N-benzylbenzamide and the known tracer molecule [(11)C]trans-N-[5-(2-flurophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofurane-1(3H),1'-cyclohexane]-4'-carboxamide ([(11)C]MK-0233), a ligand for the neuropeptide Y Y5 receptor, have been performed using this technique. Following semi-preparative HPLC purification and reformulation, 1262 ± 113 MBq of [(11)C]MK-0233 was produced at the end of the synthesis with a specific activity of 100 ± 30 GBq µmol(-1) and a >99% radiochemical purity. This corresponds to a decay corrected radiochemical yield of 7.2 ± 0.7%. Using a 3 mL vial as the reaction vessel, and following semi-preparative HPLC purification and reformulation, 1255 ± 392 MBq of [(11)C]MK-0233 was produced at the end of the synthesis with a specific activity of 100 ± 15 GBq µmol(-1) and a >99% radiochemical purity. This corresponds to a decay corrected radiochemical yield of 7.1 ± 2.2%.

Rapid carbonylative coupling reactions using palladium(I) dimers: applications to 11CO-radiolabelling for the synthesis of PET tracers.

Palladium dimers with sterically hindered phosphines have been shown to be excellent pre-catalysts for the aminocarbonylation of aryl halides to yield amides and one of them has been successfully employed as a pre-catalyst for the synthesis of (11)C-radiolabelled amides for PET imaging.

Binding and photodissociation of CO in iron(II) complexes for application in positron emission tomography (PET) radiolabelling.

(R-DAB)FeI(2) complexes containing bidentate diimide ligands (R-DAB = RN=CH-CH=NR; R = (i)Pr, c-C(6)H(11)) have been investigated for their ability to react with carbon monoxide to form iron(II) dicarbonyl complexes, (R-DAB)FeI(2)(CO)(2). Solution IR spectroscopy revealed two νCO stretches between 2000 and 2040 cm(-1) corresponding to a cis-arrangement of the carbonyl ligands around the iron. Photochemical decarbonylation was achieved by UV irradiation (365 nm), which occurred within 5 min as evidenced by solution IR spectroscopy. (c-C(6)H(11)-DAB)FeI(2) has been characterised by X-ray crystallography. Reactions using (11)C-labelled carbon monoxide were investigated and revealed that both (R-DAB)FeI(2) species were not effective as trapping complexes due to the low concentrations of [(11)C]CO used in these experiments. A Fe(TPP)(THF)(x) (TPP = tetraphenylporphyrin) complex was investigated with unlabelled CO and the monocarbonyl adduct Fe(TPP)(THF)CO was formed in situ as identified by IR spectroscopy (νCO = 1966 cm(-1)) yet was stable to CO loss upon UV irradiation. Carbonylation reactions of in situ-generated Fe(TPP)(THF)(x) using [(11)C]CO revealed that 97% of the [(11)C]CO stream could be trapped in one pass of the gas at room temperature and at atmospheric pressure.

Copper(I) scorpionate complexes and their application in palladium-mediated [(11)C]carbonylation reactions.

Solutions of copper(I) tris(pyrazolyl)borate complexes have been used to greatly improve the solubility of [(11)C]carbon monoxide, enabling it to be used in low-pressure, 'one-pot' palladium-mediated carbonylation reactions to form (11)C-radiolabelled amides and ureas for use in positron emission tomography.

ScorpoPhos: a novel phosphine-nitrogen ligand containing a tris(pyrazolyl)borate ligand core.

A new tris(pyrazolyl)borate ligand bearing phosphine donor groups appended to the 3-position of the pyrazolyl rings is reported, and the hemilabile behaviour of this tris-N,P ligand in coordination with K+, Tl+ and Cu+ ions is investigated.

A novel tetrakis(pyrazolyl)borate ligand bearing triphenylphosphine oxide substituents.

A new tetrakis(pyrazolyl)borate ligand bearing triphenylphosphine oxide moieties appended to the 3-position of the pyrazolyl rings is reported and shown to display varied coordination chemistry from tridentate N(2)O coordination with thallium to hexadentate N(3)O(3) coordination with europium.

Variable coordination behaviour of pyrazole-containing N,P and N,P(O) ligands towards palladium(II).

Three bidentate, mixed-donor ligands based on a triphenylphosphine unit bearing a pyrazole group in the ortho-position of one phenyl ring have been synthesised; the N,P ligand [2-(3-pyrazolyl)phenyl]diphenylphosphine pzphos has been synthesised and transformed into new N,P(O) and N,P(S) derivatives, [2-(3-pyrazolyl)phenyl]diphenylphosphine oxide pzphos(O) and [2-(3-pyrazolyl)phenyl]diphenylphosphine sulfide pzphos(S), respectively. The coordination chemistry of pzphos and pzphos(O) towards palladium(II) has been investigated. Depending on the ligand to metal molar ratio employed in the reactions of palladium(II) with pzphos, either the 1 : 1 chelate [Pd(pzphos)Cl2] 1a or the 2 : 1 N,P chelate [Pd(pzphos)2]Cl2 1b was obtained. 1b contains two six-membered chelate rings in which the chlorides have been displaced from the inner coordination sphere of palladium. Exchange of the chloride anions in 1b for perchlorate anions was achieved using AgClO4 to give [Pd(pzphos)2][ClO4]2 1c. Reaction of pzphos(O) under the same conditions forms the 2 : 1 adduct [Pd(pzphos(O))2Cl2] 2b regardless of the metal to ligand ratio or the order of addition of reactants. Unlike the N,P chelate 1b, the N,P(O) ligands in complex 2b bind in a monodentate fashion through the N-donor atoms of the pyrazole rings. Abstraction of the chloro ligands in compound 2b using AgClO4 gave the 2 : 1 N,P(O) chelate [Pd{pzphos(O)}2][ClO4]2 2c, in which entropically unfavourable 7-membered chelate rings are formed. X-Ray diffraction has been used to confirm the solid-state structures of the pzphos(O) ligand and the complexes 1b, 1c, 2b and 2c.