No abstract

Labeling derivatives of dihydrotetrabenazine (DTBZ) with F-18 (T 1/2 = 110 min) instead of C-11 (T 1/2 = 20 min), would improve their utility and availability for imaging vesicular monoamine transporters (VMAT2) in clinical settings. The successful synthesis, reported previously, of two novel 9-fluoroalkyl(±)-DTBZ ligands prompted us to study the optically resolved active ligand 9-fluoropropyl-(+)-DTBZ (FP-(+)-DTBZ), which may have more promising characteristics. The inhibition constant (Ki) estimated for FP-(+)-DTBZ (using [ 3 H](±)-DTBZ as the labeled ligand in rat striatal homogenates) showed a lower value as compared to the racemic FP-(±)-DTBZ (0.10 ± 0.01 vs 0.19 ± 0.04 nM). The inactive isomer, FP-(−)-DTBZ, displayed a much lower binding affinity with a K i value >3000 nM. Biodistribution studies in mice after an iv injection of [ 18 F]FP-(+)-DTBZ exhibited a ratio of striatum (ST, target) to cerebellum (CB, background) of 4.51 at 30 minutes postinjection, which is a higher value than previously obtained with the racemic ligand [ 18 F]FP-(±)-DTBZ (ST/CB = 2.95). Brain extraction at 30 minutes after the tracer injection in mice showed that >95% of the radioactivity corresponded to the parent, non-metabolized, compound remaining in the striatum, suggesting that the tracer has an excellent in vivo stability. Furthermore, localization of the tracer in the brain examined with ex vivo autoradiography displayed a typical distribution pattern consistent with VMAT2 sites. The highest labeling was observed in monoaminergic neuron regions (caudate putamen, olfactory tubercle, nucleus accumbens, substania nigra, dorsal raphe and locus coerules). We also tested the selective labeling of this tracer at the dopamine neurons in unilaterallesioned mice (treated with 6-hydroxydopamine). When [ 18 F]FP-(+)-DTBZ and [ 125 I]IPT ((N-(3'-iodopropen-2'-yl)-2-beta-carbomethoxy-3-beta-(4-chlorophenyl)tropane, a selective marker for dopamine transporters in dopaminergic neurons) were simultaneously injected into lesioned mice, we observed an excellent correlation (r = 0.95) for these tracers. From these findings, we conclude that [ 18 F]FP-(+)-DTBZ is a sensitive and selective tracer for VMAT2 binding sites and it may be useful for in vivo evaluation of diseases relating to changes of monoamine neuronal integrity.

The specific binding and regional brain pharmacokinetics of new fluorine-18 labeled radioligands for the vesicular monoamine transporter (VMAT2) were examined in the rat and primate brain. In the rat, 9-

[reaction: see text]. Metal carbenoid chemistry is used to convert delta-amino beta-ketoesters into 5-substituted 3-oxo prolines, which expands the utility of this class of polyfunctionalized chiral building blocks.

Alkylation reactions using alpha-halolactams or lactam enolates derived from bicyclic lactam templates can proceed with high endo- or exo- diastereoselectivity respectively. In the latter case, stereochemical correction by means of enolate generation and hindered phenol quench is possible with moderate efficiency. This protocol has been applied to the synthesis of protected penmacric acid and its analogues.