A General Copper‐Mediated Nucleophilic 18F Fluorination of Arenes

Molecules labeled with fluorine‐18 are used as radiotracers for positron emission tomography. An important challenge is the labeling of arenes not amenable to aromatic nucleophilic substitution (S_NAr) with [¹⁸F]F^?. In the ideal case, the ¹⁸F fluorination of these substrates would be performed through reaction of [¹⁸F]KF with shelf‐stable readily available precursors using a broadly applicable method suitable for automation. Herein, we describe the realization of these requirements with the production of ¹⁸F arenes from pinacol‐derived aryl boronic esters (arylBPin) upon treatment with [¹⁸F]KF/K₂₂₂ and [Cu(OTf)₂(py)₄] (OTf=trifluoromethanesulfonate, py=pyridine). This method tolerates electron‐poor and electron‐rich arenes and various functional groups, and allows access to 6‐[¹⁸F]fluoro‐L ‐DOPA, 6‐[¹⁸F]fluoro‐m‐tyrosine, and the translocator protein (TSPO) PET ligand [¹⁸F]DAA1106.     

Radiofluorination of a Pre‐formed Gallium(III) Aza‐macrocyclic Complex: Towards Next‐Generation Positron Emission Tomography (PET) Imaging Agents

As part of a study to investigate the factors influencing the development of new, more effective metal‐complex‐based positron emission tomography (PET) imaging agents, the distorted octahedral complex, [GaCl(L)]?2 H₂O has been prepared by reaction of 1‐benzyl‐1,4,7‐triazacyclononane‐4,7‐dicarboxylic acid hydrochloride (H₂L?HCl) with Ga(NO₃)₃?9 H₂O, which is a convenient source of Ga^III for reactions in water. Spectroscopic and crystallographic data for [GaCl(L)]?2 H₂O are described, together with the crystal structure of [GaCl(L)]?MeCN. Fluorination of this complex by Cl^?/F^? exchange was achieved in high yield by treatment with KF in water at room temperature over 90 minutes, although the reaction was complete in approximately 30 minutes if heated to 80 °C, giving [GaF(L)]?2 H₂O in good yield. The same complex was obtained by hydrothermal synthesis from GaF₃?3 H₂O and Li₂L, and has been characterised by single‐crystal X‐ray analysis, IR, ¹H and ¹⁹F{¹H} NMR spectroscopy and ESI⁺ MS. Radiofluorination of the pre‐formed [GaCl(L)]?2 H₂O has been demonstrated on a 210 nanomolar scale in aqueous NaOAc at pH 4 by using carrier‐free ¹⁸F^?, leading to 60–70 % ¹⁸F‐incorporation after heating to 80 °C for 30 minutes. The resulting radioproduct was purified easily by using a solid‐phase extraction (SPE) cartridge, leading to 98–99 % radiochemical purity. The [Ga¹⁸F(L)] is stable for at least 90 minutes in 10 % EtOH/NaOAc solution at pH 6, but defluorinates over this time scale at pH of approximately 7.5 in phosphate buffered saline (PBS) or human serum albumin (HSA). The subtle role of the Group 13 metal ion and co‐ligand donor set in influencing the pH dependence of this system is discussed in the context of developing potential new imaging agents for PET.     

A Practical One-Pot Synthesis of Positron Emission Tomography (PET) Tracers via Nickel-Mediated Radiofluorination

Invited for this months cover picture is the group of Professor Bernd Neumaier at the Institute of Radiochemistry and Experimental Molecular Imaging at the University Clinic of Cologne. The cover picture shows the differences in brain metabolism of a healthy young and a healthy old subject, as well as a patient suffering from Parkinsons disease (left to right) uncovered by 6-[¹⁸F]FDOPA-positron emission tomography (PET). Morbus Parkinson occurs when nerve cells that produce dopamine begin to die. The shortage of dopamine leads to movement problems in affected individuals. 6-[¹⁸F]FDOPA is extensively used to evaluate the progression of Parkinsons disease. Bold stick projections of this PET tracer, as well as a neuronal network, are seen in the background. Unfortunately, conventional procedures to produce 6-[¹⁸F]FDOPA are cumbersome. Thus, several recent developments aim at the simplification of this radiosynthesis. In our work, we studied the applicability of the recently reported Ni-mediated radiofluorination approach for daily routine production of 6-[¹⁸F]FDOPA. For more details, see the Full Paper on p. 457 ff.     

A Highly Efficient Copper‐Mediated Radioiodination Approach Using Aryl Boronic Acids

A convenient and quantitative radioiodination method by copper‐mediated cross‐coupling of aryl boronic acids was developed. The mild labeling conditions, ready availability of the boronic acid substrate, simple operation, broad functional group tolerance and excellent radiochemical yield (RCY) make this a practical strategy for radioiodine labeling without further purification.     

Pd0‐Mediated Rapid Cross‐Coupling Reactions,the Rapid C‐[11C]Methylations,Revolutionarily Advancing the Syntheses of Short‐Lived PET Molecular Probes

Positron emission tomography is a noninvasive method for monitoring drug (or diagnostic) behavior and its localization on the target molecules in the living systems, including the human body, using a short‐lived positron‐emitting radionuclide. New methodologies for introducing representative short‐lived radionuclides, ¹¹C and ¹⁸F, into the carbon frameworks of biologically active organic compounds have been established by developing rapid C‐[¹¹C]methylations and C‐[¹⁸F]fluoromethylations using rapid Pd⁰‐mediated cross‐coupling reactions between [¹¹C]methyl iodide (sp³‐hybridized carbon) and an excess amount of organotributylstannane or organoboronic acid ester having sp²(phenyl, heteroaromatic, or alkenyl), sp(alkynyl), or sp³(benzyl and cinnamyl)‐hybridized carbons; and [¹⁸F]fluoromethyl halide (iodide or bromide) and an organoboronic acid ester, respectively. These rapid reactions provide a firm foundation for an efficient and general synthesis of short‐lived ¹¹C‐ or ¹⁸F‐labeled PET molecular probes to promote in vivo molecular imaging studies.     

Carbon‐11 Radiolabelling of Organosulfur Compounds: 11C Synthesis of the Progesterone Receptor Agonist Tanaproget

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

Cover Picture: A Practical One-Pot Synthesis of Positron Emission Tomography (PET) Tracers via Nickel-Mediated Radiofluorination (ChemistryOpen 4/2015)

Invited for this months cover picture is the group of Professor Bernd Neumaier at the Institute of Radiochemistry and Experimental Molecular Imaging at the University Clinic of Cologne. The cover picture shows the differences in brain metabolism of a healthy young and a healthy old subject, as well as a patient suffering from Parkinsons disease (left to right) uncovered by 6-[¹⁸F]FDOPA-positron emission tomography (PET). Morbus Parkinson occurs when nerve cells that produce dopamine begin to die. The shortage of dopamine leads to movement problems in affected individuals. 6-[¹⁸F]FDOPA is extensively used to evaluate the progression of Parkinsons disease. Bold stick projections of this PET tracer, as well as a neuronal network, are seen in the background. Unfortunately, conventional procedures to produce 6-[¹⁸F]FDOPA are cumbersome. Thus, several recent developments aim at the simplification of this radiosynthesis. In our work, we studied the applicability of the recently reported Ni-mediated radiofluorination approach for daily routine production of 6-[¹⁸F]FDOPA. For more details, see the Full Paper on p. 457 ff.     

Copper‐64‐Alloyed Gold Nanoparticles for Cancer Imaging: Improved Radiolabel Stability and Diagnostic Accuracy

Gold nanoparticles, especially positron‐emitter‐ labeled gold nanostructures, have gained steadily increasing attention in biomedical applications. Of the radionuclides used for nanoparticle positron emission tomography imaging, radiometals such as ⁶⁴Cu have been widely employed. Currently, radiolabeling through macrocyclic chelators is the most commonly used strategy. However, the radiolabel stability may be a limiting factor for further translational research. We report the integration of ⁶⁴Cu into the structures of gold nanoparticles. With this approach, the specific radioactivity of the alloyed gold nanoparticles could be freely and precisely controlled by the addition of the precursor ⁶⁴CuCl₂ to afford sensitive detection. The direct incorporation of ⁶⁴Cu into the lattice of the gold nanoparticle structure ensured the radiolabel stability for accurate localization in vivo. The superior pharmacokinetic and positron emission tomography imaging capabilities demonstrate high passive tumor targeting and contrast ratios in a mouse breast cancer model, as well as the great potential of this unique alloyed nanostructure for preclinical and translational imaging.     

Enzyme‐Mediated Site‐Specific Bioconjugation of Metal Complexes to Proteins: Sortase‐Mediated Coupling of Copper‐64 to a Single‐Chain Antibody

The enzyme‐mediated site‐specific bioconjugation of a radioactive metal complex to a single‐chain antibody using the transpeptidase sortase A is reported. Cage amine sarcophagine ligands that were designed to function as substrates for the sortase A mediated bioconjugation to antibodies were synthesized and enzymatically conjugated to a single‐chain variable fragment. The antibody fragment scFv_anti‐LIBS targets ligand‐induced binding sites (LIBS) on the glycoprotein receptor GPIIb/IIIa, which is present on activated platelets. The immunoconjugates were radiolabeled with the positron‐emitting isotope ⁶⁴Cu. The new radiolabeled conjugates were shown to bind selectively to activated platelets. The diagnostic potential of the most promising conjugate was demonstrated in an in vivo model of carotid artery thrombosis using positron emission tomography. This approach gives homogeneous products through site‐specific enzyme‐mediated conjugation and should be broadly applicable to other metal complexes and proteins.     

Synthesis and Bioimaging of Positron‐Emitting 15O‐Labeled 2‐Deoxy‐D‐glucose of Two‐Minute Half‐Life

In positron emission tomography (PET), which exploits the affinity of a radiopharmaceutical for the target organ, a systematic repertoire of oxygen‐15‐labeled PET tracers is expected to be useful for bioimaging owing to the ubiquity of oxygen atoms in organic compounds. However, because of the 2‐min half‐life of ¹⁵O, the synthesis of complex biologically active ¹⁵O‐labeled organic molecules has not yet been achieved. A state‐of‐the‐art synthesis now makes available an ¹⁵O‐labeled complex organic molecule, 6‐[¹⁵O]‐2‐deoxy‐D ‐glucose. Ultrarapid radical hydroxylation of 2,6‐dideoxy‐6‐iodo‐D ‐glucose with molecular oxygen labeled with ¹⁵O of two‐minute half‐life provided the target ¹⁵O‐labeled molecule. The labeling reaction with ¹⁵O was complete in 1.3 min, and the entire operation time starting from the generation of ¹⁵O‐containing dioxygen by a cyclotron to the purification of the labeled sugar was 7 min. The labeled sugar accumulated in the metabolically active organs as well as in the bladder of mice and rats. ¹⁵O‐labeling offers the possibility of repetitive scanning and the use of multiple PET tracers in the same body within a short time, and hence should significantly expand the scope of PET studies of small animals.     

Yttrium‐86 Is a Positron Emitting Surrogate of Gadolinium for Noninvasive Quantification of Whole‐Body Distribution of Gadolinium‐Based Contrast Agents

Gadolinium‐based contrast agents (GBCAs) are used to provide diagnostic information in clinical magnetic resonance (MR) examinations. Gadolinium (Gd) has been detected in the brain, bone and skin of patients, months and years following GBCA administration, raising concerns about long term toxicity. Despite increased scrutiny, the concentration, chemical form and fate of the retained gadolinium species remain unknown. Importantly, the whole body biodistribution and organ clearance of GBCAs is poorly understood in humans. Gadolinium lacks suitable isotopes for nuclear imaging. We demonstrate that the yttrium‐86 isotope can be used as a gadolinium surrogate. We show that Gd and their analogous Y complexes have similar properties both in solution and in vivo, and that yttrium‐86 PET can be used to track the biodistribution of GBCAs over a two‐day period.     

Copper‐Mediated Aminoquinoline‐Directed Radiofluorination of Aromatic C−H Bonds with K18F

A Cu‐mediated ortho‐C?H radiofluorination of aromatic carboxylic acids that are protected as 8‐aminoquinoline benzamides is described. The method uses K¹⁸F and is compatible with a wide range of functional groups. The reaction is showcased in the high specific activity automated synthesis of the RARβ2 agonist [¹⁸F]AC261066.     

Metal-ion-dependent biological properties of a chelator-derived somatostatin analogue for tumour targeting

Somatostatin-based radioligands have been shown to have sensitive imaging properties for neuroendocrine tumours and their metastases. The potential of [(55)Co(dotatoc)] (dotatoc =4,7,10-tricarboxymethyl-1,4,7,10-tetraazacyclododecane-1-ylacetyl-D-Phe-(Cys-Tyr-D-Trp-Lys-Thr-Cys)-threoninol (disulfide bond)) as a new radiopharmaceutical agent for PET has been evaluated. (57)Co was used as a surrogate of the positron emitter (55)Co and the pharmacokinetics of [(57)Co(dotatoc)] were investigated by using two nude mouse models. The somatostatin receptor subtype (sst1-sst5) affinity profile of [(nat)Co(dotatoc)] on membranes transfected with human somatostatin receptor subtypes was assessed by using autoradiographic methods. These studies revealed that [(57)Co(dotatoc)] is an sst2-specific radiopeptide which presents the highest affinity ever found for the sst2 receptor subtype. The rate of internalisation into the AR4-2J cell line also was the highest found for any somatostatin-based radiopeptide. Biodistribution studies, performed in nude mice bearing an AR4-2J tumour or a transfected HEK-sst2 cell-based tumour, showed high and specific uptake in the tumour and in other sst-receptor-expressing tissues, which reflects the high receptor binding affinity and the high rate of internalisation. The pharmacologic differences between [(57)Co(dotatoc)] and [(67)Ga(dotatoc)] are discussed in terms of the structural parameters found for the chelate models [Co(II)(dota)](2-) and [Ga(III)(dota)](-) whose X-ray structures have been determined. Both chelates show six-fold coordination in pseudo-octahedral arrangements.     

Organofluorosilanes as Model Compounds for 18F‐Labeled Silicon‐Based PET Tracers and their Hydrolytic Stability: Experimental Data and Theoretical Calculations (PET=Positron Emission Tomography)

Water stable! Radiochemists have recently discovered silicon chemistry as a tool for the introduction of ¹⁸F into biomolecules for positron emission tomography (PET) imaging. ¹⁸F‐labeled PET tracers must be stable towards defluorination under physiological conditions. Here, a theoretical model of organofluorosilane hydrolysis is developed that correlates with the experimentally determined hydrolytic half‐lives and allows estimation of the stability of newly designed compounds (see scheme).