Synthesis of [ 18 F]GBR 12909, a dopamine reuptake inhibitor

Preparation of no‐carrier‐added fluorine‐18 labeled GBR 12909 (1‐[2‐(bis(4‐fluorophenyl)methoxy)ethyl]‐4‐(3‐phenylpropyl)piperazine), a specific and high affinity inhibitor of dopamine reuptake, is described. 4‐Fluoro‐4′‐[ 18 F]fluorobenzophenone was prepared by [ 18 F]fluoride ion substitution of the corresponding trimethylammonium trifluoromethanesulfonate salt. The [ 18 F]benzophenone was reduced to the benzhydrol, chlorinated, then used to alkylate 1‐(2‐hydroxyethyl)‐4‐(3‐phenyl‐propyl)piperazine to yield [ 18 F]GBR 12909 in high specific activity (≥2000 Ci/mmol) and overall yields of 10–16% (corrected, 140 min synthesis).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90171/1/2580280708_ftp.pd

Regional brain distribution of [18F]GBR 13119, a dopamine uptake inhibitor, in CD-1 and C57BL/6 mice

We have examines the regional brain distribution of [18F]GBR 13119 (18F: [beta]+, T1/2 = 110 min), a dopamine uptake inhibitor, in CD-1 and C57BL/6 mice. High levels of binding are observed in the striatum of both species, with striatum/cerebellum ratios of 3-4 at 60 min after injection of the radiotracer. Striatum radioactivity and striatum/cerebellum ratios are more than 50% reduced in C57BL/6 mice treated chronically with the neurotoxin MPTP. We conclude mice are an appropriate model for the in vivo study of the dopamine uptake system, and that [18F]GBR 13119 may be a suitable in vivo marker for degeneration of striatal dopaminergic neurons.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27847/1/0000258.pd

Synthesis of fluorine-18 labeled GABA uptake inhibitors

The first syntheses of fluorine-18 labeled inhibitors of GABA reuptake [(R,S)-1-{2-{4-[18F]fluorophenyl}phenyl}methoxyethyl]piperidine-3-carboxylic acid, (R,S)-1-{2-(4-[18F]fluorophenyl)(4-fluorophenyl)methoxyethyl}piperidine-3-carboxylic acid, and (R,S)-1-[2-{(4-[18F]trifluoromethyl)phenyl} {(4-trifluoromethyl)phenyl}-methoxyethyl]piperidine-3-carboxylic acid] are described. These N-substituted nipecotic acid derivatives were prepared in no-carrier-added form by the condensation of the appropriately substituted [18F]benzhydryl chlorides (prepared in three steps from [18F]fluoride ion) with N-(2-hydroxyethyl)nipecotic acid ethyl ester, followed by ester hydrolysis. Overall radiochemical yields were 17-28% (corrected, 150 min synthesis time). A simple new method for synthesis of a [18F]trifluoromethyl group by the nucleophilic substitution of a bromodifluoromethyl substituent has also been developed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28921/1/0000758.pd

Mouse brain distribution of a carbon-11 labeled vesamicol derivative: Presynaptic marker of cholinergic neurons

The regional mouse brain distribution of a new carbon-11 labeled derivative of vesamicol, [11C]-5-(N-methylamino)benzovesamicol ([11C]MABV) is reported. Radiotracer concentrations in vivo are in the rank order of striatum>cortex>hippocampus>hypothalamus> cerebellum, consistent with reported distributions of other presynaptic cholinergic neuronal markers. In time course studies, striatum/cerebellum and cortex/cerebellum ratios for (-)-[11C]MABV continue to increase to values of 13 and 5, respectively, 75 min after i.v. injection of [11C]MABV. The specific binding in striatum and cortex is lowered by pretreatment with (+/-)-vesamicol, and shows stereoselectivity with lower uptake and lower ratios for the (+)-enantiomer. (-)-[11C]MABV is proposed as a positron-emitting radioligand for the in vivo study of presynaptic cholinergic neurons.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28961/1/0000798.pd

In vivo binding of the dopamine uptake inhibitor [18F]GBR 13119 in MPTP-treated C57BL/6 mice

The in vivo regional distribution of [18F]GBR 13119 (1-[(4-[18F]fluorophenyl(phenyl)methoxy)ethyl]-4-(3-phenylpropyl) piperazine), a specific dopamine reuptake inhibitor, was examined in brains of C57BL/6 mice after MPTP treatment. At 2 weeks post MPTP the in vivo specific binding of [18F]GBR 13119 in striatum was decreased 63% relative to age and sex-matched controls. Animals studied at 6 and 8 weeks after MPTP treatment showed a gradual recovery of specific [18F]GBR 13119 binding in the striatum. No significant changes were observed in binding of radiotracer to cerebellum or cortex after MPTP treatment, nor were age-related changes observed in control mice. In vivo radiotracer studies thus appear useful for following gradual changes in the dopamine uptake system of mouse brain after neurotoxin treatment.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29646/1/0000735.pd

Shades of grey: Radiopharmaceutical chemistry in the 1990s and beyond

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29931/1/0000288.pd

[18F]fluorination/decarbonylation: New route to aryl [18F]fluorides

A new route to aryl [18F]fluorides without electron withdrawing ring substituents has been developed. [18F]Fluorobenzaldehydes, prepared from no-carrier-added (NCA) [18F]fluoride using nucleophilic aromatic substitution of fluoro or nitro groups, were decarbonylated using palladium on charcoal (Pd-C). By this approach 2-methoxy-4-nitrobenzaldehyde was converted to NCA 3-[18F]fluorophenol (25-30%, EOB) and 4-fluoro-2-methoxy-5-methylbenzaldehyde to carrier-added (CA) 3-[18F]fluoro-4-methylphenol (30-40%, EOB). Overall synthesis time was about 2 h. Since the 4-fluoro-2-methoxy-5-methylbenzaldehyde was in turn prepared by methylation and regiospecific formylation of 3-fluoro-4-methylphenol, the overall process represents use of a removable activating group for nucleophilic aromatic substitution with [18F]fluoride for preparation of CA and NCA aryl [18F]fluorides.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29665/1/0000754.pd

Synthesis and regional mouse brain distribution of [11C]Nisoxetine, a norepinephrine uptake inhibitor

Nisoxetine, a selective and high affinity (IC50 = 1 nM) inhibitor of NE reuptake, has been radiolabeled in high specific activity (> 600 Ci/mmol) by the alkylation of the nor-methyl precursor with [11C]CH3I. Synthetic yields are good (40-60% from [11C]methyl iodide, corrected for decay, 20 min synthesis), with the product purified by HPLC. In vivo studies of regional brain distribution in CD-1 mice show uptake and retention of tracer in the cortex, striatum, hypothalamus and thalamus, with the highest levels in the hypothalamus and cortex. Specific binding in the cortex and hypothalamus can be reduced by preadministration of 7mg/kg i.v. unlabeled nisoxetine. The possible value of [11C]nisoxetine as a PET imaging agent is discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28228/1/0000681.pd

Synthesis of [18F]flunarizine

Flunarizine, a calcium channel antagonist of the piperazine class, has been labeled with the positron-emitter 18F. 4-[18F]Fluoro-4'-fluorobenzhydryl chloride was prepared in three steps from no-carrier-added [18F]fluoride ion, and used in the alkylation of N-cinnamylpiperazine to give [18F]flunarizine in 13% radiochemical yield (from [18F]fluoride).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29547/1/0000635.pd