Pretargeted imaging can be used to visualize and quantify slow accumulating targeting vectors with short-lived radionuclides such as fluorine-18 - the most clinically applied Positron Emission Tomography (PET) radionuclide. Pretargeting...
Aliphatic nucleophilic substitution (S N 2) with [ 18 F]fluoride is the most widely applied method to prepare 18 F-labeled positron emission tomography (PET) tracers. Strong basic conditions commonly used during 18 F-labeling procedures inherently limit or prohibit labeling of base-sensitive scaffolds. The high basicity stems from the tradition to trap [ 18 F]fluoride on anion exchange cartridges and elute it afterward with basic anions. This sequence is used to facilitate the transfer of [ 18 F]fluoride from an aqueous to an aprotic organic, polar reaction medium, which is beneficial for S N 2 reactions. Furthermore, this sequence also removes cationic radioactive contaminations from cyclotron-irradiated [ 18 O]water from which [ 18 F]fluoride is produced. In this study, we developed an efficient elution procedure resulting in low basicity that permits S N 2 18 F-labeling of base-sensitive scaffolds. Extensive screening of trapping and elution conditions (>1000 experiments) and studying their influence on the radiochemical yield (RCY) allowed us to identify a suitable procedure for this. Using this procedure, four PET tracers and three synthons could be radiolabeled in substantially higher RCYs (up to 2.5-fold) compared to those of previously published procedures, even from lower precursor amounts. Encouraged by these results, we applied our low-basicity method to the radiolabeling of highly base-sensitive tetrazines, which cannot be labeled using state-of-art direct aliphatic 18 F-labeling procedures. Labeling succeeded in RCYs of up to 20%. We believe that our findings facilitate PET tracer development by opening the path toward simple and direct S N 2 18 F fluorination of base-sensitive substrates.
Gamma-hydroxybutyric acid (GHB) is an important analyte in clinical and forensic toxicology with a narrow detection window of 3-6 h. In the search of improved detection methods, the existence in vivo of a glucuronated GHB metabolite (GHB-GLUC) was hypothesized. Chemically pure standards of GHB-GLUC and a deuterated analogue for chromatography were synthesized. Liquid chromatography and tandem mass spectrometry were used for targeted analysis in anonymous clinical urine samples (n = 50). GHB-GLUC was found in concentrations ranging from 0.11 to 5.0 µg/mL (mean: 1.3 ± 1.2 µg/mL). Thus far, this is the first report of a GHB glucuronide detected in biological samples. Given that glucuronides generally have longer half-life values than their corresponding free drugs, GHB-GLUC should theoretically be a biomarker of GHB intoxication. It is also proposed that the hitherto unexplained reports of elevated GHB concentrations in some biological samples, which has caused the setting of a relatively high cutoff value (10 µg/mL), represent total GHB measurements (sum of free GHB and actively chemically hydrolyzed GHB-GLUC). To address these challenges, the present study must be followed by comprehensive pharmacokinetic and stability studies after the controlled administration of GHB.
Gc-globulin scavenges actin released from necrotic he-the central nervous system with hepatic encephalopapatocytes to the extracellular space. In 77 patients with thy. 1 fulminant hepatic failure (FHF) (excluding patients A major problem in the treatment of FHF is the decitreated with liver transplantation), admission levels of sion of orthotopic liver transplantation (OLTx). [2][3][4][5] Early serum Gc-globulin and degree of complexing with mono-identification of patients at risk of dying is essential meric actin (complex ratio) were determined to evaluate to avoid irreversible damages, primarily brain damage their predictive values in relation to survival/nonsur-caused by cerebral edema. Despite a number of studies vival. Gc-globulin levels were significantly reduced in 47 in this area, [6][7][8][9][10][11][12] center to center because of etiological differences or ratio in nonsurvivors did not differ significantly from that of survivors. Gc-globulin levels were significantly differences in the expression of apparent identical dislower in 59 patients with non-acetaminophen-induced eases. FHF, compared with 18 patients with acetaminophen-Gc-globulin is a plasma protein that is synthesized induced FHF (P õ .01). Using a cutoff level of serum Gc-in the liver and abundant in the organism. The most globulin of 100 mg/L, a lesser value correctly predicted important function is to clear actin, released from dying nonsurvival in 79% of patients with non-acetamino-or dead liver cells, from the extracellular space. Gcphen-induced FHF, whereas a higher value predicted globulin binds avidly to the monomeric form of actin, survival in 60%. In patients with acetaminophen-G-actin, and acts in combination with gelsolin in the induced FHF, nonsurvival was correctly predicted in extracellular actin scavenger system. [13][14][15][16] In pathologi-100% of patients and survival in 53%. In comparison, the cal conditions with widespread cell necrosis, the extraKing's College Hospital (KCH) criteria correctly predicted nonsurvival and survival in 69% and 57%, respec-cellular actin scavenger system may be exhausted, and tively, of the same non-acetaminophen-induced FHF free actin-polymers may cause microthrombi in capilpatients and in 60% and 38%, respectively, of the acet-laries and arterioles. 17 In animals and in smaller series aminophen-induced FHF patients. Thus, in our study in man, Gc-globulin levels have been shown to be repopulation, the predictive properties of Gc-globulin duced in FHF. [18][19][20][21][22] In one study with seven patients, were in the same range as the KCH criteria. An advan-nonsurvivors had lower Gc-globulin levels and a higher tage of Gc-globulin is that it gives an estimate of the complex ratio (i.e., degree of complexing with G-actin) outcome already on admission. Acute liver transplanta-than survivors. 21 Recently, a study including 47 FHF tion should be considered in FHF patients with Gc-globpatients with mainly acetaminophen poisoning showed ulin less than 100 mg/L. (HEPATOLOGY 1996;23:713-718.) ...
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