Standardization of fluorine-18 manufacturing processes: new scientific challenges for PET.

In [(18)F]fluoride chemistry, the minute amounts of radioactivity taking part in a radiolabeling reaction are easily outnumbered by other reactants. Surface areas become comparably larger and more influential than in standard fluorine chemistry, while leachables, extractables, and other components that normally are considered small impurities can have a considerable influence on the efficiency of the reaction. A number of techniques exist to give sufficient (18)F-tracer for a study in a pre-clinical or clinical system, but the chemical and pharmaceutical understanding has significant gaps when it comes to scaling up or making the reaction more efficient. Automation and standardization of [(18)F]fluoride PET tracers is a prerequisite for reproducible manufacturing across multiple PET centers. So far, large-scale, multi-site manufacture has been established only for [(18)F]FDG, but several new tracers are emerging. In general terms, this transition from small- to large-scale production has disclosed several scientific challenges that need to be addressed. There are still areas of limited knowledge in the fundamental [(18)F]fluoride chemistry. The role of pharmaceutical factors that could influence the (18)F-radiosynthesis and the gaps in precise chemistry knowledge are discussed in this review based on a normal synthesis pattern.

Toward modeling H-NOX domains: a DFT study of heme-NO complexes as hydrogen bond acceptors.

Density functional theory calculations (PW91/STO-TZP, including basis-set superposition error corrections) have been used to evaluate hydrogen bond energies of five- and six-coordinate heme-NO complexes with phenol and imidazole, chosen as models for distal pocket tyrosine and histidine residues. The calculated interaction energies are approximately 2 kcal/mol for phenol and 3-4 kcal/mol for imidazole, which are 2-4 times smaller than the energies calculated for heme-O(2) complexes hydrogen-bonding with a distal histidine. Interestingly, the hydrogen bond energies are found to be very similar for five- and six-coordinate heme-NO complexes, which may be viewed as contrary to the interpretation of a recent observation on a bacterial H-NOX (Heme-Nitric oxide/OXygen-binding) protein with sequence homology to mammalian-soluble guanylate cyclase.

Understanding the unexpected linearity of the trans-{Mn(NO)2}8 unit in a phthalocyanine complex: some thoughts on dinitrosylheme intermediates in biology.

Simple MO arguments provide a qualitative explanation for the near-linear ON-Mn-NO arrangement observed for the trans-{Mn(NO)2}8 anion [Mn(Pc)(NO)2]-, which is unexpected for an Enemark-Feltham electron count n>6. The metal center in this species may be described as low-spin d6("t2g6") and the two unpaired electrons occupy a pair of eu orbitals composed of NO(pi*) components, giving rise to a triplet ground state. In a certain sense, these eu SOMOs may be likened to the SOMO (singly occupied molecular orbital) of the allyl radical. The electronic structure of this species is quite different from that of diamagnetic dinitrosylheme intermediates, which have been spectroscopically characterized in synthetic studies as well as proposed for soluble guanylate cyclase and cytochrome c'. Some speculative remarks are offered as to why this proposal is not an unreasonable one from an electronic-structural perspective.