[en] GR89696, racemic methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl) methyl] -1-piperazinecarboxylate, a kappa opioid receptor ligand, was labeled with [¹¹C]methyl chloroformate. The radiochemical yield was 20% with an observed specific radioactivity of 75.5 GBq/μmol at end of synthesis (2,040 mCi/μmol). Five minutes after intravenous administration, 5.4% of the injected dose accumulated in mouse whole brain. Brain region to cerebellar ratios increased over time with ratios at 90 min of 7.8, 5.6, and 4.5 for the hypothalamus, olfactory tubercle, and striatum, respectively. The uptake of [¹¹C]GR89696 correlated with known kappa opioid receptor densities and was inhibited by kappa opioid selective drugs

[en] The R and S enantiomers of [¹¹C]GR89696, [¹¹C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)methyl] -1-piperazinecarboxylate, were synthesized from their appropriate chiral precursors and [¹¹C]methyl chloroformate. The [¹¹C]-labeled R enantiomer of GR89696, also known as GR103545, demonstrated high affinity in mouse brain with region to cerebellar ratios at 90 minutes of 11.4 and 8.7 for the hypothalamus and olfactory tubercle, respectively. The [¹¹C]-labeled S enantiomer showed low affinity and region to cerebellar ratios of 1 for all brain regions. The [¹¹C]-labeled GR103545 exhibited a selective and saturable binding for the kappa opioid receptor

[en] [¹¹C]A-69024, (±)-1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2- [¹¹C]methyl-1,2,3,4-tetrahydroisoquinoline, is a specific and selective dopamine D1 radiotracer. The in vivo biodistribution of this novel radioligand in mice showed a high uptake in the striatum (6.7% ID/g) at 5 min, followed by clearance with a half-life of 16.1 min. As a measure of specificity, the striatal/cerebellar ratio reached a maximum of 7.4 at 30 min post-injection. Radioactivity in the striatum was reduced to the level of the cerebellum by pre-administration of the D1 antagonist SCH 23390 (1 mg/kg). Pretreatment of mice with spiperone (D2), 7-hydroxydipropylaminotetralin (7-OH-DPAT) (D3), clozapine (D4), ketanserin (5-HT2/5-HT2C), mazindol (monoamine reuptake), prazosin (α₁), and haloperidol (D2/σ) had no inhibitory effect on [¹¹C]A-69024 uptake in the striatum. The dextrotatory enantiomer of the dopamine antagonist butaclamol inhibited striatal uptake, while the less active isomer (-)-butaclamol did not. [¹¹C]A-69024 binding was inhibited by unlabeled A-69024 in a dose dependent manner (ED₅₀ = 0.3 mg/kg) in the striatum while no change occurred in the cerebellum. [¹¹C]A-69024 warrants further investigation as a PET ligand for examination of central dopamine D1 receptors in humans.

[en] An improved procedure that facilitates routine production and increases the radiochemical yield of [¹¹C]McN5652 (trans - 1,2,3,5,6,10b-hexahydro-6-[4-([¹¹C]methylthio)-phenyl]pyrrolo-[2,1-a]- isoquinoline) is presented. Specifically, thiol acetate, butyrate, and benzoate derivatives of McN5652 were prepared as the precursors for the [¹¹C]McN5652 synthesis. These thioesters offer greater stability than the previously used thiol precursor (desmethyl McN5652) and enable a single batch of material to be used for multiple radiolabelings. Hydrolysis of the thioester functionality (tetrabutylammonium hydroxide, 10 min) unmasked the free thiol which, without purification, was reacted with [¹¹C]iodomethane in DMF at 40-45 deg. C for 1 min. The average decay-corrected radiochemical yield for [¹¹C]McN5652 was 26% with an average specific activity of 2290 mCi/μmol (end of synthesis). This facile radiolabeling method, utilizing the butyrate thioester of McN5652, was also employed in the preparation of [³H](+)- and (-)McN5652 [trans-1,2,3,5,6S (or 6R), 10bR, (or 10bS)-hexahydro-6-[4-([³H]methylthio)phenyl]pyrrolo-[2,1,a]-isoquinoline] from [³H]iodomethane

[en] A radiosynthetic method to prepare the nicotinic acetylcholine receptor radioligand (S)-5-[¹²³I]iodo-3-(2-azetidinylmethoxy)pyridine, 5-IA, has been developed. The two-step sequence produced [¹²³I]-5-IA in high radiochemical yield (52%), high radiochemical purity (98%), and high specific radioactivities (>8,500 mCi/μmol). Preliminary single photon emission computed tomography studies with [¹²³I]-5-IA in baboon demonstrated the appropriate regional localization for a high-affinity nicotinic radioprobe (thalamus > frontal cortex > cerebellum). Pretreatment with cytisine blocked [¹²³I]-5-IA uptake in all brain regions (78-59% reduction), demonstrating the specificity of the radiotracer

[en] [¹⁸F] SR144385 and [¹⁸F] SR147963 were synthesized in a multistep reaction in which fluorine-18 was introduced by nucleophilic halogen displacement on a bromo precursor. The fluorine-18-labeled intermediate was deprotected and coupled with the appropriate alkyl amine to give the final products. Both radioligands had appropriate regional brain distribution for cannabinoid receptors with a target to nontarget ratio of 1.7 for [¹⁸F] SR147963 and 2.5 for [¹⁸F] SR144385 at 60 and 90 min postinjection, respectively. The uptake of both tracers was blocked with a 1 mg/kg dose of SR141716A

[en] The in vivo brain regional distribution of 2-[¹⁸F]fluoro-A-85380, a novel tracer for positron emission tomographic (PET) studies, followed the regional densities of brain nAChRs reported in the literature. Evidence of binding to nAChRs and high specificity of the binding in vivo was demonstrated by inhibition with nAChR selective ligands as well as with unlabeled 2-fluoro-A-85380. A preliminary toxicology study of the 2-fluoro-A-85380 showed a relatively low biological effect. 2-[¹⁸F]Fluoro-A-85380 holds promise as a useful radiotracer for imaging of nAChRs with PET

[en] A selective ligand for the dopamine transporter 3β-(4-iodophenyl)tropan-2β-carboxylic acid isopropyl ester (RTI-121) has been labeled with iodine-125 by electrophilic radioiododestannylation. The [¹²⁵I]RTI-121 was obtained in good yield (86 ± 7%, n = 3) with high radiochemical purity (>99%) and specific radioactivity (1210-1950 mCi/μmol). After i.v. administration of [¹²⁵I]RTI-121 to mice, the rank order of regional brain tissue radioactivity (striatum > olfactory tubercles >> cortex, hippocampus, thalamus, hypothalamus, cerebellum) was consistent with dopamine transporter labeling. Specific in vivo binding in striatum and olfactory tubercles was saturable, and was blocked by the dopamine transporter ligands GBR 12,909 and (±)-nomifensine. By contrast, binding was not reduced by paroxetine, a serotonin transporter inhibitor, or desipramine, a norepinephrine transporter inhibitor. A variety of additional drugs having high affinities for recognition sites other than the neuronal dopamine transporter also had no effect. The [¹²⁵I]RTI-121 binding in striatum and olfactory tubercles was inhibited by d-amphetamine in dose-dependent fashion. Nonmetabolized radioligand represents 85% of the signal observed in extracts of whole mouse brain. Thus, [¹²⁵I]RTI-121 is readily prepared, and is a useful tracer for dopamine transporter studies in vivo

[en] 6-[¹⁸F]Fluoro-3-(2(S)-azetidinylmethoxy)pyridine (6-[¹⁸F]fluoro-A-85380 or 6-[¹⁸F]FA), a new tracer for positron emission tomography, was synthesized by no-carrier-added [¹⁸F] fluorination of 6-iodo-3-((1-tert-butoxycarbonyl-2(S)-azetidinyl)methoxy)pyridine followed by acidic deprotection. 6-[¹⁸F]FA followed the regional densities of brain nicotinic acetylcholine receptors (nAChRs) reported in the literature. Evidence of binding to nAChRs and high specificity of the binding in vivo was demonstrated by inhibition with nAChR selective ligands as well as with unlabeled 6-FA. A preliminary toxicology study of the 6-FA showed a relatively low biological effect

[en] The selective, reversible acetylcholinesterase inhibitor 5,7-Dihydro-7-methyl-3- -4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol3-6-one (CP-126,998) was labeled with C-11 iodomethane via base-promoted alkylation of the lactam nitrogen. [¹¹C] CP-126,998 was synthesized in good radiochemical yield (13-29% non-decay corrected) and high specific radioactivity (177-418 GBq/μmol). In vivo mouse biodistribution studies reveal [¹¹C] CP-126,998 to localize preferentially in striatal tissue, a region known to be rich in acetylcholinesterase. Competitive blocking studies using a variety of acetylcholinesterase inhibitors (diisopropylfluorophosphate, tacrine, CP-118,954) verified the specificity of the PET radiotracer for brain acetylcholinesterase