Steven Kealey

Transition metal mediated [11C]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.

Evaluation of 11C-BU99008, a PET Ligand for the Imidazoline2 Binding Sites in Rhesus Brain

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 11C via methylation. The in vivo binding properties of 11C-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: 11C-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 11C-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 11C-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 11C-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 11C-BU99008 to the clinic.

Imaging Imidazoline-I2 Binding Sites in Porcine Brain Using 11C-BU99008

Changes in the density of imidazoline-I2 binding sites have been observed in a range of neurologic disorders including Alzheimers disease, Huntingtons chorea, and glial tumor; however, the precise function of these sites remains unclear. A PET probe for I2 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 I2 ligand from autoradiography studies, displaying high affinity and good selectivity toward the target. In this study, BU99008 was radiolabeled with 11C in order to image the I2 binding sites in vivo using PET. Methods: 11C-BU99008 was radiolabeled by N-alkylation of the desmethyl precursor using 11C-methyl iodide. A series of PET experiments was performed to investigate the binding of 11C-BU99008 in porcine brains, in the presence or absence of a nonradiolabeled, competing I2 ligand, BU224. Results: 11C-BU99008 was obtained in good yield and specific activity. In vivo, 11C-BU99008 displayed good brain penetration and gave a heterogeneous distribution with high uptake in the thalamus and low uptake in the cortex and cerebellum. 11C-BU99008 brain kinetics were well described by the 1-tissue-compartment model, which was used to provide estimates for the total volume of distribution (VT) across brain regions of interest. Baseline VT values were ranked in the following order: thalamus > striatum > hippocampus > frontal cortex ≥ cerebellum, consistent with the known distribution and concentration of I2 binding sites. Administration of a selective I2 binding site ligand, BU224, reduced the VT to near-homogeneous levels in all brain regions. Conclusion: 11C-BU99008 appears to be a suitable PET radioligand for imaging the I2 binding sites in vivo.

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.

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.

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.

Carbon-11 Radiolabelling of Organosulfur Compounds: 11C 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.

Synthesis and in vivo evaluation of [11C]BU99008 as a ligand for the imidazoline I2 binding site

Background: Imidazoline−2 binding sites (I2BS) are thought to be mainly located on glial cells, and have prompted interest in neurodegenerative and neuro-inflammatory conditions where glia function is altered (e.g. Alzheimers disease [1], glial tumors [2, 3] and Parkinsons disease [4, 5]). In vitro studies showed that compound BU99008 has a high affinity and selectivity towards the I2BS (Ki=1.4± 0.8 nM) making it a potential candidate for PET labelling and in vivo investigations. This abstract reports the synthesis and initial preclinical in vivo characterization of [C]BU99008.

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

Ammonium [11C]thiocyanate, produced from [11C]CS2, was used to efficiently radiolabel a range of C-11 thiocyanate and thiazolone molecules.

Transition metal mediated [11C]carbonylation reactions: recent advances and applications: Special issue of JLCR ‘current developments in PET and SPECT imaging’

[(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.