Two-Injection Start Regimen of Long-Acting Aripiprazole in 133 Patients With Schizophrenia.

PURPOSE/BACKGROUND: Based on a population-pharmacokinetic model, the European Medicines Agency has recently approved a simplified starting strategy of aripiprazole once a month (AOM), injectable and long-acting antipsychotic, with two 400 mg injections and a single oral 20 mg dose of aripiprazole, administered on the same day, instead of 1 injection and 14 daily administrations of concurrent oral aripiprazole. However, to our knowledge, no previous study has reported the safety and tolerability of this regimen in real-world patients. METHODS/PROCEDURES: We retrospectively reviewed medical records of 133 patients who received the newly approved 2-injection start regimen as part of their standard care in 10 Italian clinical centers. FINDINGS/RESULTS: Adverse effects were mild or moderate, with no clinically evident difference from the adverse effects observed in previous trials where AOM was started with a single injection followed by 14 days of orally administered aripiprazole. None of the patients who started AOM after the 2-injection start regimen experienced severe adverse effects or severe adverse effects. IMPLICATIONS/CONCLUSIONS: The coadministration of 2 injections of 400 mg aripiprazole and 20 mg oral aripiprazole was not associated with safety concerns beyond those reported after a single injection followed by 14 days of orally administered aripiprazole. Our results should be interpreted with caution, due to the limited sample size and to the retrospective design of the study.

Himic Anhydride: A Retro Diels-Alder Reaction for the Organic Laboratory and an Accompanying NMR Study.

The thermal equilibration of himic anhydride [IUPAC (2-endo,3-endo)-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride] to (2-exo,3-exo)-bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid anhydride and subsequent recrystallization of the exo-product can be performed as a standard undergraduate laboratory experiment requiring minimal equipment. The interpretation of the 1H NMR spectra for these norbornene carboxylic anhydride molecules promotes an appreciation of constrained ring systems and factors that affect chemical shifts and coupling constants.

Inorganic approaches for radiolabelling biomolecules with fluorine-18 for imaging with positron emission tomography.

Conventional methods for radiolabelling biomolecules such as proteins and peptides with fluorine-18 for PET imaging rely on carbon-fluorine bond formation and are complex and inefficient. Several non-carbon elements form strong bonds (i.e. with high bond enthalpy) with fluorine, but with lower activation energy for their formation compared to carbon-fluorine bonds, whilst preserving a relatively high kinetic stability. In particular, by incorporating boron-, aluminium- and silicon-containing prosthetic groups into biomolecules, promising results have recently been achieved in the radiolabelling with F-18-fluoride under mild aqueous conditions, affording a level of convenience, efficiency and specific activity potentially superior to those offered by conventional C-F bond formation methods. The promise already shown by these early studies heralds a new branch of bioconjugate radiochemistry involving a wider range of "fluoridephilic" elements for synthesis of PET molecular imaging agents.

Synthesis and evaluation of analogues of HYNIC as bifunctional chelators for technetium.

6-Hydrazinonicotinic acid (HYNIC, 1) is a well-established bifunctional technetium-binding ligand often used to synthesise bioconjugates for radiolabelling with Tc-99m. It is capable of efficient capture of technetium at extremely low concentrations, but the structure of the labelled complexes is heterogeneous and incompletely understood. In particular, it is of interest to determine whether, at the no-carrier-added level, it acts in a chelating or non-chelating mode. Here we report two new isomers of HYNIC: 2-hydrazinonicotinic acid (2-HYNIC, 2), which (like 1) is capable of chelation through the mutually ortho hydrazine and pyridine nitrogens and 4-hydrazinonicotinic acid (4-HYNIC, 3), which is not (due to the para-relationship of the hydrazine and pyridine nitrogens). LC-MS shows that the coordination chemistry of 2 with technetium closely parallels that of conventional 1, and no advantages of one over the other in terms of potential labelling efficiency or isomerism were discernable. Both 1 and 2 formed complexes with the loss of 5 protons from the ligand set, whether the co-ligand was tricine or EDDA. Ligand 3, however, failed to complex technetium except at very high ligand concentration: the marked contrast with 1 and 2 suggests that chelation, rather than nonchelating coordination, is a key feature of technetium coordination by HYNIC. Two further new HYNIC analogues, 2-chloro-6-hydrazinonicotinic acid (2-chloro-HYNIC, 4a) and 2,6-dihydrazinonicotinic acid (diHYNIC, 5) were also synthesised. The coordination chemistry of 4a with technetium was broadly parallel to that of 1 and 2 although it was a less efficient chelator, while 5 also behaved as an efficient chelator of technetium, but its coordination chemistry remains poorly defined and requires further investigation before it can sensibly be adopted for (99m)Tc-labelling. The new analogues 4a and 5 present an opportunity to develop trifunctional HYNIC analogues for more complex bioconjugate synthesis.

Technetium-binding in labelled HYNIC-peptide conjugates: role of coordinating amino acids.

Electrospray mass spectrometry (ESMS) of certain peptides labelled with (99m)Tc via hydrazinonicotinamide (HYNIC) with tricine as co-ligand shows one Tc-bound tricine, whereas typically two are observed. We speculated that this was due to coordination of a neighbouring histidine (His) or glutamate (Glu). To investigate this possibility, several short peptides incorporating lysine (HYNIC), with and without His and Glu at different positions in the sequence, were radiolabelled with (99m)Tc, using tricine, ethylenediaminediacetic acid (EDDA) and nicotinic acid as co-ligands. The products were examined by HPLC-ESMS, cysteine challenge and bovine serum albumin (BSA) challenge. Peptides with His nearby on either side of lysine (HYNIC) contained only one tricine and showed markedly enhanced structural homogeneity and stability to cysteine challenge and BSA binding, except those with His located at the N-terminus. Peptides without His, or with neighbouring N-terminal His, contained two tricines and were less stable to cysteine challenge and BSA binding. Glu participated in Tc-binding but did not enhance stability. We conclude that neighbouring His or Glu side chains coordinate to Tc and this could alter peptide or protein conformation. Inclusion of His in a neighbouring position to lysine (HYNIC) enhances stability, improves homogeneity and reduces the demand of the metal center for binding to additional co-ligands.

99mTc-HYNIC-Gastrin Peptides: Assisted Coordination of 99mTc by Amino Acid Side Chains Results in Improved Performance Both In Vitro and In Vivo.

UNLABELLED: The aim of this study was to determine the effects of assisted coordination by amino acids such as histidine and glutamic acid on the function of (99m)Tc-labeled gastrin peptide-hydrazinonicotinamide (HYNIC) conjugates and their ability to target cholecystokinin-R in small-animal models. METHODS: Three peptide-HYNIC conjugates containing the -AYGWMDF-NH2 C-terminal sequence and combinations of histidine, glutamic acid, and glycine were synthesized, radiolabeled with (99m)Tc/(99)Tc using either tricine or ethylenediaminediacetic acid as a coligand, and analyzed by the high-performance liquid chromatography and liquid chromatography-mass spectrometric techniques. Stability, receptor binding, and internalization and in vivo targeting in AR42J-bearing mice were assessed. RESULTS: When radiolabeling was performed using tricine as a coligand, the insertion of a histidine residue near the HYNIC residue resulted in the displacement of one molecule of tricine from the coordination sphere, a reduction in the number of radiolabeled species formed, an improvement in the in vitro stability, an increase in the rate of radiopeptide internalization, and a significant improvement in tumor uptake in vivo. When radiolabeling was performed using ethylenediaminediacetic acid as a coligand, no effect on coligand binding, homogeneity, or in vitro stability was observed but a significant improvement in the internalization in vitro and tumor uptake in vivo was again found. All of the complexes formed showed similar receptor affinity in competitive radioligand binding assays. CONCLUSION: The insertion of histidine into the sequence of peptide-HYNIC conjugates can result in more stable, more homogeneous complexes that show improvements in tumor-targeting performance both in vitro and in vivo.

A technetium intermediate specifically promotes deprotection of trifluoroacetyl HYNIC during radiolabelling under mild conditions.

The trifluoroacetyl group protects the nucleophilic HYNIC from unwanted side reactions yet allows radiolabelling with technetium-99m under mild conditions, due to efficient and specific promotion of deprotection by a technetium complex intermediate.

Metabolic side effects of second generation antipsychotic agents in antipsychotic-naïve patients: one-month prospective evaluation.

The present study investigated the effects of second generation antipsychotics (SGA) on the metabolism of 15 antipsychotic-naïve outpatients. Evaluations were performed at baseline and after 1 month of treatment. A significant increase in mean body mass index (BMI) and mean waist circumference was observed. These results suggest the importance of monitoring patients from the first few weeks of antipsychotic treatment.

How do HYNIC-conjugated peptides bind technetium? Insights from LC-MS and stability studies.

Hydrazinonicotinamide (HYNIC) is an established bifunctional complexing agent for technetium-99m ((99m)Tc) but the structure of the technetium coordination sphere remains uncertain. To gain further insight into this, we have prepared conjugates of HYNIC and hydrazinobenzoic acid (HYBA) with a model peptide, and radiolabelled them with (99m)Tc using three well-established co-ligand systems: EDDA, tricine and tricine-nicotinic acid. The labelled peptides were studied by LC-MS and by subjecting them to serum stability and protein binding assays. For each co-ligand system, HYNIC conjugates formed fewer and more stable labelled species than the corresponding HYBA conjugates. LC-MS analysis showed that all conjugates contained one hydrazine moiety bound to Tc, that binding of Tc to HYNIC-peptide and co-ligand occurs with displacement of 5H(+) indicating a Tc formal oxidation state of +5, and that the Tc has no oxo- or halide ligands. LC-MS also shows that complexes formed with the HYNIC conjugate contain fewer coordinating co-ligand molecules than the HYBA conjugate indicating that HYNIC is able to more effectively satisfy the coordination requirement of technetium, perhaps by binding in chelating mode.

Trifluoroacetyl-HYNIC peptides: synthesis and 99mTc radiolabeling.

Fmoc-lys(HYNIC-Boc)-OH, a precursor for solid-phase synthesis of 99mTc-labeled peptides, was synthesized efficiently without HPLC purification. HPLC-ESMS showed that deprotection and decoupling of peptide from the resin with trifluoroacetic acid gave initially HYNIC-peptide, which was trifluoroacetylated upon prolonged incubation. The trifluoroacetyl-HYNIC group was hydrolyzed during 99mTc labeling, rendering deprotection unnecessary. Trifluoroacetyl-HYNIC peptide was 99mTc-labeled as efficiently, producing the same product, as HYNIC-peptide. These modifications enhance the versatility of HYNIC for 99mTc peptide labeling.

Anion binding in (arene)ruthenium(II)-based hosts?

Asymmetric ruthenium(II) complexes of a flexible aminomethylpyridine derivative exhibit diastereotopic ligand methylene protons, as measured by NMR spectroscopy; binding of external anions renders these protons equivalent possibly by increasing dynamically averaged symmetry; the amount of anion needed to raise average symmetry correlates to the anion binding constant.