Current trends in the use of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) in neurooncology.

The diagnostic potential of PET using the amino acid analogue O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) in brain tumor diagnostics has been proven in many studies during the last two decades and is still the subject of multiple studies every year. In addition to standard magnetic resonance imaging (MRI), positron emission tomography (PET) using [18F]FET provides important diagnostic data concerning brain tumor delineation, therapy planning, treatment monitoring, and improved differentiation between treatment-related changes and tumor recurrence. The pharmacokinetics, uptake mechanisms and metabolism have been well described in various preclinical studies. The accumulation of [18F]FET in most benign lesions and healthy brain tissue has been shown to be low, thus providing a high contrast between tumor tissue and benign tissue alterations. Based on logistic advantages of F-18 labelling and convincing clinical results, [18F]FET has widely replaced short lived amino acid tracers such as L-[11C]methyl-methionine ([11C]MET) in many centers across Western Europe. This review summarizes the basic knowledge on [18F]FET and its contribution to the care of patients with brain tumors. In particular, recent studies about specificity, possible pitfalls, and the utility of [18F]FET PET in tumor grading and prognostication regarding the revised WHO classification of brain tumors are addressed.

Expanding PET-applications in life sciences with positron-emitters beyond fluorine-18.

Positron-emission-tomography (PET) has become an indispensable diagnostic tool in modern nuclear medicine. Its outstanding molecular imaging features allow repetitive studies on one individual and with high sensitivity, though no interference. Rather few positron-emitters with near favourable physical properties, i.e. carbon-11 and fluorine-18, furnished most studies in the beginning, preferably if covalently bound as isotopic label of small molecules. With the advancement of PET-devices the scope of in vivo research in life sciences and especially that of medical applications expanded, and other than "standard" PET-nuclides received increasing significance, like the radiometals copper-64 and gallium-68. Especially during the last decades, positron-emitters of other chemical elements have gotten into the focus of interest, concomitant with the technical advancements in imaging and radionuclide production. With known nuclear imaging properties and main production methods of emerging positron-emitters their usefulness for medical application is promising and even proven for several ones already. Unfortunate decay properties could be corrected for, and ß+-emitters, especially with a longer half-life, provided new possibilities for application where slower processes are of importance. Further on, (bio)chemical features of positron-emitters of other elements, among there many metals, not only expanded the field of classical clinical investigations, but also opened up new fields of application. Appropriately labelled peptides, proteins and nanoparticles lend itself as newer probes for PET-imaging, e.g. in theragnostic or PET/MR hybrid imaging. Furthermore, the potential of non-destructive in-vivo imaging with positron-emission-tomography directs the view on further areas of life sciences. Thus, exploiting the excellent methodology for basic research on molecular biochemical functions and processes is increasingly encouraged as well in areas outside of health, such as plant and environmental sciences.

Baeyer-Villiger oxidation tuned to chemoselective conversion of non-activated [18 F]fluorobenzaldehydes to [18 F]fluorophenols.

A reaction pathway via oxidation of [18 F]fluorobenzaldehydes offers a very useful tool for the no-carrier-added radiosynthesis of [18 F]fluorophenols, a structural motive of several potential radiopharmaceuticals. A considerably improved chemoselectivity of the Baeyer-Villiger oxidation (BVO) towards phenols was achieved, employing 2,2,2-trifluoroethanol as reaction solvent in combination with Oxone or m-CPBA as oxidation agent. The studies showed the necessity of H2 SO4 addition, which appears to have a dual effect, acting as catalyst and desiccant. For example, 2-[18 F]fluorophenol was obtained with a RCY of 97% under optimised conditions of 80°C and 30-minute reaction time. The changed performance of the BVO, which is in agreement with known reaction mechanisms via Criegee intermediates, provided the best results with regard to radiochemical yield (RCY) and chemoselectivity, i.e. formation of [18 F]fluorophenols rather than [18 F]fluorobenzoic acids. Thus, after a long history of the BVO, the new modification now allows an almost specific formation of phenols, even from electron-deficient benzaldehydes. Further, the applicability of the tuned, chemoselective BVO to the n.c.a. level and to more complex compounds was demonstrated for the products n.c.a. 4-[18 F]fluorophenol (RCY 95%; relating to 4-[18 F]fluorobenzaldehyde) and 4-[18 F]fluoro-m-tyramine (RCY 32%; relating to [18 F]fluoride), respectively.

Cis-4-[18F]fluoro-D-proline detects neurodegeneration in patients with akinetic-rigid parkinsonism.

OBJECTIVES: This study aimed to investigate whether the amino acid PET tracer cis-4-[F]fluoro-D-proline [D-cis-[F]FPro] shows increased uptake in the basal ganglia of patients with neurodegenerative akinetic-rigid parkinsonism. D-Cis-[F]FPro is a sensitive PET tracer for inflammation-associated neurodegeneration in animal models. We hypothesized that D-cis-[F]FPro might also be a sensitive marker of alterations of the basal ganglia in parkinsonian syndromes. PARTICIPANTS AND METHODS: Ten patients with neurodegenerative akinetic-rigid parkinsonism (five with idiopathic Parkinson's disease and five with atypical parkinsonian syndromes) were imaged with D-cis-[F]FPro and compared with 13 patients with brain tumors who had no basal ganglia involvement. PET images 20-50 min after injection were evaluated and tracer uptake in the basal ganglia was quantified using volume-of-interest analysis with basal ganglia to background ratios. The severity of disease was assessed with unified Parkinson's disease rating scale III and correlated with D-cis-[F]FPro uptake. RESULTS: In patients with parkinsonism, volume-of-interest analysis showed mild, but significantly increased D-cis-[F]FPro uptake in the basal ganglia, pronounced in the lenticular nucleus. Disease severity correlated with D-cis-[F]FPro uptake in the right pallidum (r=-0.687, P=0.041). CONCLUSION: Data suggest that D-cis-[F]FPro is a sensitive marker of inflammation-associated degenerative processes in parkinsonian syndromes.

Treatment-Related Uptake of O-(2-18F-Fluoroethyl)-l-Tyrosine and l-[Methyl-3H]-Methionine After Tumor Resection in Rat Glioma Models.

Assessment of residual tumor after resection of cerebral gliomas can be difficult with MRI and may be improved by amino acid PET. The aim of this experimental study was to investigate uptake of 2-18F-fluoroethyl-l-tyrosine (18F-FET) and l-[methyl-3H]-methionine (3H-MET) in residual tumor after surgery and possible false-positive uptake in treatment-related changes. Methods: F98 or GS-9L rat gliomas were implanted into the brain of 64 rats. Tumors were resected after 1 wk of tumor growth, and sham surgery was performed in an additional 10 animals. At different time points after surgery (1, 2, 3, 7, and 14-16 d), rats underwent ex vivo dual-tracer autoradiography using 18F-FET and 3H-MET. Histologic slices were evaluated by immunostaining for cell density and astrogliosis. Tracer uptake was quantified by lesion-to-brain ratios (L/B) at the rim of the resection cavity (considered treatment-related uptake) and in residual or recurrent tumor tissue. Four animals showing no residual tumor underwent PET 3 d after surgery to examine time-activity curves of 18F-FET uptake in treatment-related changes. Results: Treatment-related uptake with a mean L/B of 2.0 ± 0.3 for 18F-FET and a mean L/B of 1.7 ± 0.2 for 3H-MET was noted at the rim of the resection cavity in the first week after surgery, decreasing significantly by 14-16 d (P < 0.01). Treatment-related tracer uptake was significantly higher for 18F-FET than for 3H-MET (P < 0.001). Tracer uptake in rat gliomas exceeded treatment-related tracer uptake at all time points (P < 0.001), but the latter was in the range of human gliomas. Reactive astrogliosis was noted near the resection cavity from the second day after surgery. Time-activity curves of 18F-FET uptake in those areas revealed constantly increasing uptake. Conclusion: Surgery may induce significant treatment-related 18F-FET and 3H-MET uptake near the resection cavity in the first week after surgery, presumably caused by reactive astrogliosis. Treatment-related tracer uptake was less pronounced for 3H-MET, indicating that 11C-MET may be better suited for assessing the postoperative situation than 18F-FET. Assessment of residual tumor after surgery by amino acid PET seems to be more reliable after an interval of 14 d.

52g/55Mn-Labelled CDTA-based trimeric complexes as novel bimodal PET/MR probes with high relaxivity.

trans-1,2-Diaminocyclohexane-N,N,N',N'-tetraacetic acid (CDTA) labelled with a mixture of paramagnetic 55Mn(ii) and ß+-emitting 52gMn(ii) offers access to bimodal Positron Emission Tomography/Magnetic Resonance (PET/MR) tracers. To enhance the number of NMR-active nuclei and simultaneously improve the longitudinal relaxivity r1, a complex composed of three CDTA units was designed. Accordingly, a functionalised tris-CDTA-1,3,5-tris-triazolobenzene was prepared and labelled with c.a. and n.c.a. 52gMn. Relaxivity measurements of the 55Mn-complex showed an enhancement of r1 of 144% in comparison to the Mn-CDTA monomer. Moreover, the trimer was equipped with an additional linker functionality suitable for conjugation with biomolecules, enabling interaction with specific molecular targets.

Consensus nomenclature rules for radiopharmaceutical chemistry - Setting the record straight.

Over recent years, within the community of radiopharmaceutical sciences, there has been an increased incidence of incorrect usage of established scientific terms and conventions, and even the emergence of 'self-invented' terms. In order to address these concerns, an international Working Group on 'Nomenclature in Radiopharmaceutical Chemistry and related areas' was established in 2015 to achieve clarification of terms and to generate consensus on the utilisation of a standardised nomenclature pertinent to the field. Upon open consultation, the following consensus guidelines were agreed, which aim to.

Novel CDTA-based, Bifunctional Chelators for Stable and Inert MnII Complexation: Synthesis and Physicochemical Characterization.

In the search for MnII MR and PET/MR imaging agents with optimal balance between thermodynamic stability, kinetic inertness, and relaxivity, two novel bifunctional MnII chelators (BFMnCs) based on CDTA (trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid) were synthesized. A six-step synthesis, involving the buildup of a functionalized trans-1,2-diaminocyclohexane core, provided CuAAC-reactive 6a and 6b bearing an alkyne or azide substituent on the cyclohexane ring, respectively (CuAAC = CuI-catalyzed azide-alkyne 1,3-dipolar cycloaddition). Thermodynamic, kinetic, and relaxometric studies were performed with 4-HET-CDTA (8a) as a "model chelator," synthesized in two steps from 6a. The protonation constants revealed that 8a is slightly less basic than CDTA and forms a MnII complex of marginally lower thermodynamic stability (log KMnL = 13.80 vs 14.32, respectively), while the conditional stability constant is almost identical for both chelates (pMn = 8.62 vs 8.68, respectively). Kinetic assessment of the CuII-mediated transmetalation of [Mn(4-HET-CDTA)]2- showed that proton-assisted complex dissociation is slightly slower than for [Mn(CDTA)]2- (k1 = 297 vs 400 M-1 s-1, respectively). Importantly, the dissociation half-life near physiological conditions (pH 7.4, 25 °C) underlined that [Mn(4-HET-CDTA)]2- is ∼35% more inert (t1/2 = 16.2 vs 12.1 h, respectively). Those findings may be accounted for by a combination of reduced basicity and increased rigidity of the ligand. Analysis of the 17O NMR and 1H NMRD data attributed the high relaxivity of [Mn(4-HET-CDTA)]2- (r1 = 4.56 mM-1 s-1 vs 3.65 mM-1 s-1 for [Mn(CDTA)]2-; 20 MHz, 25 °C) to slower rotational dynamics (τR298 = 105 ps). Additionally, the fast water exchange of the complex correlates well with the value reported for [Mn(CDTA)]2- (kex298 = 17.6 × 107 vs 14.0 × 107 s-1, respectively). Given the exquisite compromise between thermodynamic stability, kinetic inertness, and relaxivity achieved by [Mn(4-HET-CDTA)]2-, appropriately designed CuAAC-conjugates of 6a/6b are promising precursors for the preparation of targeted, bioresponsive, or high relaxivity manganese-based PET/MR tracers (52g/55 MnII) and MR contrast agents (MnII).

Efficient synthesis of [18 F]FPyME: A new approach for the preparation of maleimide-containing prosthetic groups for the conjugation with thiols.

An improved high yielding radiosynthesis of the known thiol-reactive maleimide-containing prosthetic group1-[3-(2-[18 F]fluoropyridine-3-yloxy)propyl]pyrrole-2,5-dione ([18 F]FPyME) is described. The target compound was obtained by a two-step one-pot procedure starting from a maleimide-containing nitro-precursor that was protected as a Diels-Alder adduct with 2,5-dimethylfurane. Nucleophilic radiofluorination followed by heat induced deprotection through a Retro Diels Alder reaction yielded, after chromatographic isolation, [18 F]FPyME with a radiochemical yield of 20% in about 60 min overall synthesis time. A variety of other [18 F]fluoropyridine based maleimide-containing prosthetic groups should be accessible via the described synthetic strategy.