PubMed · 15512892
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R G Miller, D H Moore, C E Jackson, WALS Study Group. 2004. Western ALS Study Group.. https://doi.org/10.1080/17434470410019988
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The formation of multiple molecular ions, especially due to sodium adduct ion formation, is commonly observed in electrospray mass spectrometry and may make reproducible and sensitive quantitation difficult. The objective of this work was to investigate the underlying mechanism involved in the suppression of multiple molecular ion formation and to improve the sensitivity of detection for the two anti-neoplastic agents paclitaxel and docetaxel. The results showed that alkylamine additives could significantly improve the detection of paclitaxel and docetaxel by suppression of multiple molecular ions through preferential formation of a predominant alkylamine adduct ion. Possible binding sites, binding interactions and binding competition were investigated for the sodium adduct and alkylamine adduct ions using various experimental techniques. The formation of a predominant amine adduct ion may be due to increased surface activity in the droplet. The optimal alkylamine for both analytes was octylamine, which increased peak heights of paclitaxel and docetaxel 4.8 and 3.7-fold (n = 3), respectively. The precision of the signals for the analytes was also improved 5.7-fold. A quantitative assay in plasma for paclitaxel was partially validated for the calibration range 1.0-1000 ng/mL (r = 0.9977) when using 0.05% octylamine as a reconstitution solution additive. The limit of detection (LOD) and limit of quantitation (LOQ) were 0.5 and 0.9 ng/mL, respectively. Acceptable precision, accuracy, specificity and sample stability were demonstrated for this assay. This approach may prove useful for other analytes with similar binding sites.
Use of excess quantity of additives such as 1-hydroxybenzotriazole, 1-hydroxy-7-azabenzotriazole, or 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine could retard carbodiimide-mediated peptide coupling or aminolysis of the active esters in organic solvents generally employed in peptide chemistry. Solubility test and infrared spectroscopic data suggested that the amine components interacted with the additives to form some aggregates, which were less reactive toward acylation. The use of 0.1 equimolar additives against carboxyl components or carbodiimides was advantageous for rapid and efficient coupling reaction, especially when the carboxyl components were amino acids carrying urethane type N-protecting groups.
Two somatostatin analogues, [(99m)Tc]Demotide and [(99m)Tc]Demotate 4, were compared with [(99m)Tc]Demotate 1, a previously reported somatostatin receptor subtype 2 (sst(2)) targeting tracer. Conjugates were prepared by coupling an open-chain tetraamine chelator to D-Phe(1) of [Tyr(3)]-octreotide or [Tyr(3)]-octreotate, respectively, via a p-benzylaminodiglycolic acid spacer adopting solid-phase peptide synthesis techniques. Peptide conjugates were collected in a highly pure form after chromatographic purification. Eventually, [(99m)Tc]Demotide and [(99m)Tc]Demotate 4 were obtained in approximately 1 Ci/micromol specific activity and >96% purity after labeling under alkaline conditions. Demotide and Demotate 4 exhibited similar high binding affinities for the sst(2) expressed in AR4-2J cells with IC(50) values 0.16 and 0.10 nM, respectively. The (radio)metallated analogues [(99m)Tc]Demotide and [(99m)Tc]Demotate 4 showed equally high affinities to the sst(2) during saturation binding assays in AR4-2J cell membranes (K(d)s 0.08 and 0.07 nM, respectively). During incubation at 37 degrees C with AR4-2J cells, the radiopeptides internalized effectively via a receptor-mediated process, with [(99m)Tc]Demotate 4 exhibiting a faster internalization rate than [(99m)Tc]Demotide. After injection in athymic mice bearing sst(2)-expressing AR4-2J tumors, the radiotracers showed high and specific uptake in the tumor (>25%ID/g at 1 h) and in the sst(2)-positive organs. However, both [(99m)Tc]Demotide and [(99m)Tc]Demotate 4 showed unfavorably higher background activity, especially in the abdomen, in comparison to [(99m)Tc]Demotate 1 and are, therefore, less suited than [(99m)Tc]Demotate 1 for sst(2)-targeted tumor imaging in man.