Optimised production of technetium-94m for PET imaging by proton-irradiation of phosphomolybdic acid in cyclotron liquid target.

Natural-abundance phosphomolybdic acid (H(MoPO) ‧12HO, 0.181-0.552 g Mo/mL) solutions were irradiated with 12.

(125)I-Labelled 2-Iodoestrone-3-sulfate: synthesis, characterization and OATP mediated transport studies in hormone dependent and independent breast cancer cells.

Introduction: Organic Anion Transporting Polypeptides (OATP) are a family of membrane associated transporters that facilitate estrone-3-sulphate (E3S) uptake by hormone dependent, post-menopausal breast cancers. We have established E3S as a potential ligand for targeting hormone dependent breast cancer cells, and in this study sought to prepare and investigate radioiodinated E3S as a tool to study the OATP system.

Methods: 2- and 4-Iodoestrone-3-sulfates were prepared from estrone via aromatic iodination followed by a rapid and high yielding sulfation procedure.

Synthesis and in vitro evaluation of derivatives of the β₁-adrenergic receptor antagonist HX-CH 44.

Isopropyl- and fluoroisopropyl-amino derivatives of the β(1)-adrenergic receptor antagonist 2-[4-[3-(tert-butyl-amino)-2-hydroxypropoxy]phenyl]-3-methyl-6-methoxy-4(3H)-quinazolinone ((±)HX-CH 44) were synthesized, including a concise and efficient preparation of the core, 2-(4-hydroxyphenyl)-6-methoxy-3-methylquinazolin-4(3H)-one. In vitro binding assays showed that the fluorinated analog was selective towards β(1)-adrenergic receptors over β(2)-adrenergic and 5-HT(1A) receptors. An X-ray crystallographic characterization of the fluorinated analog is also reported.

An improved radiosynthesis of the muscarinic M2 radiopharmaceutical, [18F]FP-TZTP.

The radioligand 3-(4-(3-[(18)F]fluoropropylthio)-1,2,5-thiadiazol-3-yl)-1-methyl-1,2,5,6-tetrahydropyridine ([(18)F]FP-TZTP) is an agonist with specificity towards subtype 2 of muscarinic acetylcholine (M2) receptors. It is currently the only radiotracer available for imaging M2 receptors in human subjects with positron emission tomography. The present study reports on an improved method for the synthesis of [(18)F]FP-TZTP, automated using a GE TRACERlab FX(FN) radiosynthesis module.

Synthesis and preliminary evaluation of [(18)F]-fluoro-(2S)-Exaprolol for imaging cerebral beta-adrenergic receptors with PET.

Cerebral beta-adrenergic receptors (beta-ARs) are of interest in several disorders including Parkinson's disease, Alzheimer's disease and in particular major depressive disorder. Development of a positron emission tomography (PET) ligand for imaging beta-ARs would allow the quantification of these receptors in the living human brain so as to better understand both the pathophysiology of depression and how to improve treatment. Currently there are no radioligands suitable for this purpose.

Facile radiosynthesis of fluorine-18 labeled beta-blockers. Synthesis, radiolabeling, and ex vivo biodistribution of [18F]-(2S and 2R)-1-(1-fluoropropan-2-ylamino)-3-(m-tolyloxy)propan-2-ol.

An efficient and general method has been developed for fluorine-18 labeling of beta-blockers that possess the propanolamine moiety. A new synthetically versatile intermediate, 3-(1-(benzyloxy)propan-2-yl)-2-oxooxazolidin-5-yl)methyl 4-methylbenzenesulfonate (13), was prepared and can be conjugated to any phenoxy core. To demonstrate the synthetic methodology, fluorinated derivatives of toliprolol were prepared, namely, [(18)F]-(2S and 2R)-1-(1-fluoropropan-2-ylamino)-3-(m-tolyloxy)propan-2-ol ((2S and 2R)-[(18)F]1).

Synthesis and screening of a library of Re/Tc-based amyloid probes derived from beta-breaker peptides.

Through the development and application of a unique approach for producing Re-metallopeptides, a new class of peptide-derived probes that are designed to target beta-amyloid plaques was developed. Derivatives of a class of beta-breaker peptides having the core sequence lvffa or affvl (lower case letters represent D-amino acids) and the single amino acid chelate quinoline (SAACQ) ligand which can bind Re and (99m)Tc were prepared on an automated peptide synthesizer. Both monomeric and dimeric peptides were synthesized in modest to good yields where in select examples a biotin-containing amino acid derivative was included to act as a linker point for further conjugation to carrier proteins.

Radiosynthesis and initial evaluation of [18F]-FEPPA for PET imaging of peripheral benzodiazepine receptors.

Introduction: A novel [18F]-radiolabelled phenoxyanilide, [18F]-FEPPA, has been synthesized and evaluated, in vitro and ex vivo, as a potential positron emission tomography imaging agent for the peripheral benzodiazepine receptor (PBR).

Methods: [18F]-FEPPA and two other radiotracers for imaging PBR, namely [11C]-PBR28 and [11C]-PBR28-d3, were synthesised and evaluated in vitro and ex vivo as potential PBR imaging agents.

Results: [18F]-FEPPA is efficiently prepared in one step from its tosylate precursor and [18F]-fluoride in high radiochemical yields and at high specific activity.

Fluoro-pegylated (FPEG) imaging agents targeting Abeta aggregates.

A novel approach of producing positron emission tomography (PET) imaging agents through the formation of bioconjugates based on a pegylation-fluorination strategy resulting in fluoro-pegylated (FPEG) molecules is reported. This approach offers a simple and easy method by which to incorporate 18F in the target molecule without an appreciable increase in the lipophilicity. After 18F labeling, this convenient approach leads to PET imaging probes binding to Abeta aggregates in the brain (an important factor associated with Alzheimer's disease) using the known core structures, such as [2-(4-dimethylaminophenyl)-vinyl]-benzoxazol (3') or 2-phenylbenzothiazole (4).

A new strategy for the preparation of peptide-targeted technetium and rhenium radiopharmaceuticals. The automated solid-phase synthesis, characterization, labeling, and screening of a peptide-ligand library targeted at the formyl peptide receptor.

A new solid-phase synthetic methodology was developed that enables libraries of peptide-based Tc(I)/Re(I) radiopharmaceuticals to be prepared using a conventional automated peptide synthesizer. Through the use of a tridentate ligand derived from N-alpha-Fmoc-l-lysine, which we refer to as a single amino acid chelate (SAAC), a series of 12 novel bioconjugates [R-NH(CO)ZLF(SAAC)G, R = ethyl, isopropyl, n-propyl, tert-butyl, n-butyl, benzyl; Z = Met, Nle] that are designed to target the formyl peptide receptor (FPR) were prepared. Construction of the library was carried out in a multiwell format on an Advanced ChemTech 348 peptide synthesizer where multi-milligram quantities of each peptide were isolated in high purity without HPLC purification.

N,N-bis(2-mercaptoethyl)methylamine: a new coligand for Tc-99m labeling of hydrazinonicotinamide peptides.

Hydrazinonicotinamide (HYNIC) forms stable coordination complexes with Tc-99m when reacted with Tc(V)oxo species such as Tc-mannitol or other Tc-polyhydric complexes. However, radio-HPLC of [Tc-For-MLFK-HYNIC] labeled via Tc-polyhydric ligands demonstrated multiple radiochemical species each with unique biodistribution patterns. This is likely due to the fact that Tc can bind to the hydrazino moiety, as well as polyhydric ligands, in a variety of coordination geometries.

Bridging the gap between in vitro and in vivo imaging: isostructural Re and 99mTc complexes for correlating fluorescence and radioimaging studies.

A bifunctional ligand that is capable of forming Re and 99mTc complexes as complementary fluorescent and radioactive probes was developed. The tridentate bis(quinoline) amine ligand, which is referred to as the SAACQ system, was prepared in a single step from Fmoc protected lysine in high yield. Reaction of the SAACQ ligand with [Re(CO)3Br3]2- resulted in the formation of the SAACQ-(Re(CO)3)+complex which exhibits favorable fluorescence properties including a long lifetime and a large Stoke's shift.

A new strategy for the preparation of peptide-targeted radiopharmaceuticals based on an fmoc-lysine-derived single amino acid chelate (SAAC). automated solid-phase synthesis, NMR characterization, and in vitro screening of fMLF(SAAC)G and fMLF[(SAAC-Re(CO)3)+]G.

A tridentate single amino acid chelate (SAAC) derived from N-alpha-Fmoc-l-lysine was incorporated within a short peptide sequence using an automated peptide synthesizer. Novel derivatives of the chemotactic peptide fMLF were prepared such that the SAAC and its Re complex were selectively placed between a terminal glycine amino acid and the targeting fMLF sequence. The products, which were synthesized in parallel, were characterized by mass spectrometry and multi-NMR spectroscopy.

Bifunctional single amino acid chelates for labeling of biomolecules with the [Tc(CO)(3)](+) and [Re(CO)(3)](+) cores. Crystal and molecular structures of [ReBr(CO)(3)(H(2)NCH(2)C(5)H(4)N)], [Re(CO)(3)[(C(5)H(4)NCH(2))(2)NH]]Br, [Re(CO)(3)[(C(5)H(4)NCH(2))(2)NCH(2)CO(2)H]]Br, [Re(CO)(3)[X(Y)NCH(2)CO(2)CH(2)CH(3)]]Br (X = Y = 2-pyridylmethyl; X = 2-pyridylmethyl, Y = 2-(1-methylimidazolyl)methyl; X = Y = 2-(1-methylimidazolyl)methyl), [ReBr(CO)(3)[(C(5)H(4)NCH(2))NH(CH(2)C(4)H(3)S)]], and [Re(CO)(3)[(C(5)H(4)NCH(2))N(CH(2)C(4)H(3)S)(CH(2)CO(2))]].

The reactions of a series of potentially tridentate ligands, derived from single amino acids or amino acid analogues, with [NEt(4)](2)[ReBr(3)(CO)(3)] have been investigated. The model compounds [Re(CO)(3)Br[(2-pyridylmethyl)NH(2)]] (1) and [Re(CO)(3)[(2-pyridylmethyl)(2)NH]]Br (2) were also prepared and structurally characterized. With ligands possessing two pyridyl appendages, (2-pyridylmethyl)(2)NX (X = -CH(2)CO(2)H, -CH(2)CO(2)Et, -CH(2)CH(2)CO(2)H, -CH(2)CH(2)CO(2)Et, -CH(2)CH(2)CH(2)CH(2)CH(NHCO(2)(t)Bu)CO(2)H), complexes of the type [Re(CO)(3)(ligand)]Br (3-6) were isolated.

[Re(III)Cl(3)] core complexes with bifunctional single amino acid chelates.

The reactions of the Re(V) starting material [ReO(PPh(3))(2)Cl(3)] with ligands of the type XN(Y)Z [X = Y = 2-pyridylmethyl, Z = -CH(2)CO(2)Et (L(1)Et), -CH(2)CH(2)CO(2)Et (L(2)Et), -CH(2)CH(2)CH(2)CH(2)CH(NHCO(2)Bu(t))CO(2)H (L(3)H); X = 2-pyridylmethyl, Y = 2-(1-methylimidazolyl)methyl, Z = -CH(2)CO(2)Et (L(4)Et)] yielded the Re(III) trichloride complexes of the type [ReCl(3)(L(n)R)]. The complexes are mononuclear, paramagnetic species with a facial geometry of the chloride ligands. The nitrogen donors of the tridentate L(n)()R ligands complete the distorted octahedral coordination spheres of the complexes.

Synthesis of boroxifen, a nido-carborane analogue of tamoxifen.

A nido-carborane analogue of tamoxifen, the widely employed breast cancer therapy agent, was prepared as an archetype of a potential new class of antiestrogen and boron neutron capture therapy agent in which the carborane is incorporated within the framework of the parent compound. The carborane was introduced through the reaction of 6,9-bis(acetonitrile)decaborane with a unique and highly conjugated ene-yne, which was prepared stereoselectively. NMR spectroscopy and a crystal structure of a key intermediate, the carborane analogue of chloro-tamoxifen, demonstrated the structural similarities between the tamoxifen carboranes and their corresponding phenyl analogues.