Optimized Treatment and Recovery of Irradiated [18O]-Water in the Production of [18F]-Fluoride

Enriched [18O]-water is the target material for [18F]-fluoride production. Due to its high price and scarce availability, an increased interest and necessity has arisen to recycle the used water, in order to use it multiple times as a target material for [18F]-fluoride production. This paper presents an efficient treatment and reprocessing procedure giving rise to high chemical quality [18O]-water, thereby maintaining its enrichment grade. The reprocessing is subdivided into two main steps. In the first step, the [18F]-FDG (fluorodeoxyglucose) synthesis preparation was modified to preserve the enrichment grade. Anhydrous acetonitrile is used to dry tubing systems and cartridges in the synthesis module. Applying this procedure, the loss in the enrichment throughout the reprocessing is <1%. The second step involves a fractional distillation in which the major part of the [18O]-water was recycled. Impurities such as solvents, ions, and radioactive nuclides were almost completely separated. Due to the modified synthesis preparation using acetonitrile, the first distillation fraction contains a larger amount of an azeotropic [18O]-water/acetonitrile mixture. This fraction is not further distillable. Contents of the remaining [18O]-water were separated from the azeotropic mixture by using a molecular sieve desiccant. This process represents a fast, easy, and inexpensive method for reprocessing used [18O]-water into new [18O]-water quality for further application

Synthesis, radiosynthesis, in vitro and first in vivo evaluation of a new matrix metalloproteinase inhibitor based on γ-fluorinated α-sulfonylaminohydroxamic acid

Abstract Background To study MMP activity in vivo in disease, several radiolabeled MMP inhibitors functioning as radiotracers have been evaluated by means of SPECT and PET. Unfortunately, most of them suffer from metabolic instability, mainly hepatobiliary clearance and insufficient target binding. The introduction of a fluorine atom into MMPIs could contribute to target binding, enhance the metabolic stability and might shift the clearance towards more renal elimination. Recently developed α-sulfonylaminohydroxamic acid based γ-fluorinated inhibitors of MMP-2 and -9 provide promising fluorine interactions with the enzyme active site and high MMP inhibition potencies. The aim of this study is the (radio)synthesis of a γ-fluorinated MMP-2 and -9 inhibitor to evaluate its potential as a radiotracer to image MMP activity in vivo. Results Two new fluorine-containing, enantiomerically pure inhibitors for MMP-2 and -9 were synthesized in a six step sequence. Both enantiomers exhibited equal inhibition potencies in the low nanomolar and subnanomolar range. LogD value indicated better water solubility compared to the CGS 25966 based analog. The most potent inhibitor was successfully radiofluorinated. In vivo biodistribution in wild type mice revealed predominantly hepatobiliary clearance. Two major radioactive metabolites were found in different organs. Defluorination of the radiotracer was not observed. Conclusion (Radio)synthesis of a CGS based γ-fluorinated MMP inhibitor was successfully accomplished. The (S)-enantiomer, which normally shows no biological activity, also exhibited high MMP inhibition potencies, which may be attributed to additional interactions of fluorine with enzyme’s active site. Despite higher hydrophilicity no significant differences in the clearance characteristics compared to non-fluorinated MMPIs was observed. Metabolically stabilizing effect of the fluorine was not monitored in vivo in wild type mice

Radiolabeled Selective Matrix Metalloproteinase 13 (MMP-13) Inhibitors: (Radio)Syntheses and in Vitro and First in Vivo Evaluation

The noninvasive imaging of MMP activity in vivo could have a high impact in basic research as well as in clinical applications. This approach can be established using radiolabeled MMP inhibitors (MMPIs) as tracers for the detection of activated MMPs by means of PET. However, the complexity of diseases associated with dysregulated MMP expression necessitates the imaging of distinct MMPs or MMP subgroups to distinguish their individual role in specific diseases. To this end, selective and potent MMP-13 inhibitors based on a <i>N</i>,<i>N</i>′-bis­(benzyl)­pyrimidine-4,6-dicarboxamide core have been synthesized and successfully radiolabeled with carbon-11, fluorine-18, and gallium-68. Selected radiolabeled candidates were evaluated in vitro and in vivo regarding their pharmacokinetic properties and metabolic stability

Inverse 1,2,3-Triazole-1-yl-ethyl Substituted Hydroxamates as Highly Potent Matrix Metalloproteinase Inhibitors: (Radio)synthesis, in Vitro and First in Vivo Evaluation

Noninvasive imaging and quantification of matrix metalloproteinase (MMP) activity in vivo are of great (pre)­clinical interest. This can potentially be realized by using radiolabeled MMP inhibitors (MMPIs) as positron emission tomography (PET) imaging agents. Triazole-substituted MMPIs, discovered by our group, are highly potent inhibitors of MMP-2, -8, -9, and -13. The triazole ring and its position contribute significantly to the potency of the MMP inhibitor. To evaluate structure–activity relationships (SARs) of the initially discovered triazole-substituted MMPIs, an additional CH₂-group between the backbone of the molecule and the triazole core was inserted, and the triazole ring was “inversed” by switching the alkyne and azide groups. Similar to the original triazole-substituted hydroxamates, the inverse triazole MMPIs are excellent inhibitors with promising in<i> </i>vivo properties. Pharmacokinetic properties and metabolic stability of an ¹⁸F-labeled candidate in mice were investigated

GMP-compliant radiosynthesis of [18^{18}F]GP1, a novel PET tracer for the detection of thrombi

Thrombus formation and thromboembolic events play important roles in various cardiovascular pathologies. The key receptor involved in platelet aggregation is the fibrinogen receptor glycoprotein IIb/IIIa. [$^{18}$F]GP1, a derivative of the GPIIb/IIIa antagonist elarofiban, is a specific $^{18}$F-labeled small-molecule radiotracer that binds with high affinity to GPIIb/IIIa receptors of activated platelets. An improved, robust and fully automated radiosynthesis of [$^{18}$F]GP1 has been developed. [$^{18}$F]GP1 has been synthesized with decay corrected radiochemical yields of 38 $\pm$ 6%, with a radiochemical concentration up to 1900 MBq/mL, molar activities of 952–9428 GBq/$\mu$mol and a radio-chemical purity >98%. After determination of the optimal reaction conditions, in particular for HPLC separation, adaption of the reaction conditions to PET center requirements, validation of the manufacturing process and the quality control methods, the synthesis of [$^{18}$F]GP1 was successfully implemented to GMP standards and was available for clinical application. We describe the GMP-compliant synthesis of the novel radiotracer [$^{18}$F]GP1. Moreover, we provide some proof-of-concept examples for clinical application in the cardiovascular field. PET/CT with the novel small-molecular radiotracer [18F]GP1 may serve as a novel highly sensitive tool for visualizing active platelet aggregation at the molecular level