In Vitro Ligand Binding Kinetics Explains the Pharmacokinetics of [18F]FE-PE2I in Dopamine Transporter PET Imaging.

Two of the most popular positron emission tomography (PET) tracers, [11C]PE2I and [18F]FE-PE2I, used to quantify dopamine transporters (DAT), display dissimilar kinetic behavior in in vivo assays. This difference can be explained by comparing values of kinetic rate constants, which characterize interaction of these tracers with DAT sites in vitro. At the same time, this kinetic analysis showed that the overall binding mechanism is similar for these two tracers and includes a fast step of complex formation followed by a slow isomerization step of this complex. Comparison with previous PE2I data revealed that isomerization of the DAT complex with PE2I occurs three times faster than in the case of FE-PE2I, which leads to the slower onset of peak specific binding of the former tracer in the DAT-rich regions. Therefore, ligands with slower isomerization on-rate, including [18F]FE-PE2I, seem to be better tracers in vivo, and their properties can be predicted in vitro.

Acidity of di- and triprotected hydrazine derivatives in dimethyl sulfoxide and aspects of their alkylation.

The pK(a) values in DMSO for 22 di- and triprotected hydrazine NH acids and two monosubstituted hydrazines have been determined using potentiometric titration. The results of density functional theory calculations at the B3LYP/6-311+G level of gas-phase acidities of a representative selection of mono-, di-, and trisubstituted hydrazines are compared with both the relevant published and novel experimental titration data. In the course of this work, a rough estimation of the pK(a) value of hydrazine in DMSO (ca. 38.0) has been deduced. For typical triprotected compounds of this kind containing moderately electron-withdrawing carbamate and imidodicarbonate or arenesulfonylcarbamate functions the pK(a) values fall in the range 15.1-17.3, whereas for N,N'-diprotected hydrazines with a carbamate and an aromatic sulfonyl group the corresponding values are 12.7-14.5. Several of these triprotected derivatives have recently been applied preparatively in stepwise synthesis of substituted hydrazines using alkyl halides as electrophiles in the presence of a phase transfer catalyst, and a few of them, with varying success, have been examined in model experiments with benzyl alcohol, triphenylphosphine, and diethyl azodicarboxylate in the Mitsunobu reaction. The dependence of the reactivity on the intrinsic acidity of the hydrazines in this reaction is highlighted. Furthermore, the regioselective alkylation of an N,N'-diprotected hydrazine can be rationalized on the basis of the presented data.