Vahan Papazian

Synthesis of [123I]N' N'-dimethyl-6-methyl-(4'-iodophenyl)imidazo[1,2-a]pyridine-3-acetamide for the study of Peripheral Benzodiazepine receptors using SPECT

The [123I]labelled imidazo[1,2-a]pyridine [123I]ioddozolpidem 4 was found to exhibit preferential activity towards Peripheral rather than Central Benzodiazepine receptors in vivo and was synthesised for the potential study of the Peripheral Benzodiazepine Receptors (PBR) using SPECT. [123I]Iodozolpidem was prepared from the corresponding tributyl tin precursor by iododestannylation with Na[123I] in the presence of peracetic acid or chloramine-T. Purification by semipreparative C-18 RP HPLC gave the product in radiochemical yields of 60–85%. The product was obtained in >97% chemical and radiochemical purity with a specific activity >80 GBq/μmol. Copyright

Synthesis of substituted [123I]imidazo[1,2-α]pyridines as potential probes for the study of the peripheral benzodiazepine receptors using SPECT

The imidazo[1,2-α]pyridines [N,N´-dimethyl-6-chloro-(4´zf-iodophenyl)imidazo[1,2-α]pyridine-3-acetamide 1, [N,N´l-6-chloro-(4´-iodophenyl)imidazo[1,2-α]pyridine-3-acetamide 2, and [N-methyl-6-chloro-(4´-iodophenyl)imidazo[1,2-α]pyridine-3-acetamide 3, are high affinity and selective ligands for the Peripheral Benzodiazepine Receptors (PBR). The [123I]1-3 labelled analogues of these compounds were subsequently synthesised for the potential study of the PBR in vivo using SPECT. Radioiodination was achieved by iododestannylation reactions of the corresponding tributyl tin precursors with Na[123I] in the presence of peracetic acid, chloramine-T or Iodogen. Purification of the crude product was achieved by semipreparative C-18 RP HPLC to give the products in radiochemical yields of 40-85%. The products were obtained in >97% chemical and radiochemical purity and with specific activities >80 GBq/μmol.

Synthesis and evaluation of iodine-123 labelled tricyclic tropanes as radioligands for the serotonin transporter

The tricyclic tropane analogues (1S,3S,6R,10S)-(Z)-10-(benzoyloxymethyl)-9-(3-chloro-4-iodobenzylidene)-7-azatricyclo[4.3.1.0(3,7)]decane, 1, and (1S,3S,6R,10S)-(Z)-9-(3-chloro-4-iodobenzylidene)-7-azatricyclo[4.3.1.0(3,7)]decane-10-carboxylic acid methyl ester, 2, have been shown to be potent and selective serotonin transporter (SERT) ligands. They possess nanomolar affinity for the SERT (Ki = 0.06 nM and 1.8 nM respectively) and are suitable for radiolabelling using iodine-123. In the present study we prepared [(123)I]1 and [(123)I]2 from the appropriate tributylstannane precursors using acidic media with chloramine-T as the oxidising agent. The radiochemical yield obtained for [(123)I]1 varied between 50-60% while for [(123)I]2 the range was 65-80%. Both radioligands were obtained with radiochemical purity > 97% and specific activity estimated to be > 185 GBq/micromol. The biodistribution of [(123)I]1 demonstrated low degree of brain penetration at 5 min (0.14%ID/g) with a homogeneous distribution. The radioactivity cleared quickly from all brain regions with no preferential localization. In comparison, [(123)I]2 demonstrated on average a higher brain uptake at 5 min (0.5%ID/g). However the distribution of radioactivity was homogeneous and cleared to levels similar to [(123)I]1 at 1 hr post-injection. Pre-administration of citalopram failed to show any significant inhibition of [(123)I]2 uptake in the rat brain. The high lipophilicity of 1 and 2 (HPLC-derived log P(7.4) values of 6.41 and 4.25 respectively) and in vivo metabolism, seen by high thyroid uptake would explain the absence of any specific binding observed in the rat brain. In view of these results [(123)I]1 and [(123)I]2 do not appear to be suitable radioligands for in vivo studies of the SERT.

Radiosynthesis of bromine-76 and iodine-123 labelled enantiomers of A-69024 : Radioligands for dopamine D1 receptor studies using PET and SPECT

The racemic dopamine D1 receptor antagonist A-69024 was labelled with bromine-76 for studies using PET and with iodine-123 for SPECT. [76Br]A-69024 was prepared via electrophilic bromodestannylation with NH476Br. The use of chloramine-T in acid media resulted in radiochemical yields of 70–80%. The racemic radioligand was purified by semi-preparative C-18 reverse-phase HPLC while the (+) and (−) enantiomers were separated and isolated using chiral HPLC. Average specific activities of 11 GBq/μmol were obtained. In an analogous manner, 2-[123I]A-69024 was prepared via electrophilic iododestannylation with Na123I resulting in rediochemical yields of 65–70%. Chiral HPLC gave the (+) and (−) enantiomers with specific activities of >74 GBq/μmol. The chemical and enantiomeric purity of each enantiomer of both radioligands assessed by chiral HPLC was >98%. Radiochemical purities measured by radio-TLC were >98%. The average time of synthesis for both preparations was 70 minutes. Copyright