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- aggregation classification "D1".
- aggregation creator person.
- aggregation date "2008".
- aggregation format "application/pdf".
- aggregation hasFormat 1008697.bibtex.
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- aggregation language "eng".
- aggregation publisher "Ghent University. Faculty of Pharmaceutical Sciences".
- aggregation rights "I have retained and own the full copyright for this publication".
- aggregation subject "Medicine and Health Sciences".
- aggregation title "Synthesis and in vivo evaluation of [123I]-3-I-CO: a potential SPECT tracer for the serotonin 5-HT2A receptor".
- aggregation abstract "The aim of this doctoral dissertation was the precursor synthesis, radiosynthesis and in vivo evaluation of [123I]-3-I-CO as a possible new tracer for imaging of the central serotonin 5-HT2A receptor with SPECT. [123I]-(4-fluorophenyl)[1-(3-iodophenethyl)piperidin-4-yl] methanone ([123I]-3-I-CO) demonstrates good affinity for the 5-HT2A receptor (Ki = 0.51 nM) and good selectivity ratios over other receptor types and was therefore selected as the ligand. First, the in vivo behaviour of a currently used 5-HT2A SPECT tracer, [123I]-R91150, was evaluated (chapter 3), and brain uptake of the tracer was assessed in rodents, as a standard for comparison. The influence of P-glycoprotein blocking (with cyclosporin A) on the biodistribution and brain uptake of [123I]-R91150 was also evaluated in rodents, and these results were compared with the data obtained from the normal biodistribution studies with [123I]-R91150. Also, the influence of P-glycoprotein blocking on pinhole μSPECT imaging with [123I]-R91150 in rodents was investigated. In NMRI mice, a dose-dependent influence of cyclosporin A on the brain uptake of [123I]-R91150 was observed, indicating that the increased brain uptake is the result of a decreased efflux of tracer out of the brain after blocking of the P-glycoprotein efflux transporter with cyclosporin A. Pre-treatment of Sprague-Dawley rats with cyclosporin A resulted in a drastically increased brain uptake of [123I]-R91150 (brain uptake increased seven-fold after Pglycoprotein blocking) and a vastly improved pinhole μSPECT imaging quality. From these results it can be concluded that [123I]-R91150 is a substrate for P-glycoprotein efflux in vivo, and that it’s brain efflux can be blocked by administration of cyclosporin A. Organic synthesis of the tributylstannyl precursor for the radiosynthesis of [123I]-3-I-CO was performed in adequate yield. An average yield of about 85 % was obtained in the radiosynthesis reaction. The radioligand was purified with semi-preparative HPLC, and radiochemical purities of > 95 % were obtained consistently. The radioligand was stable at room temperature until 48 h after synthesis. A logP value of 3.10 ± 0.10 was obtained for [123I]-3-I-CO (chapter 4). In vivo evaluation of [123I]-3-I-CO in NMRI mice revealed high initial brain uptake (6.26 ± 1.36 % ID/g tissue at 10 min post injection), but radioactivity concentrations in brain decreased rapidly over time. No radiolabelled metabolites were observed in blood or brain of NMRI mice. Brain uptake of [123I]-3-I-CO was also investigated in Sprague-Dawley rats (chapter 5): highest brain radioactivity concentrations were obtained in the occipital (0.942 ± 0.034 % ID/g tissue at 20 min post injection) and frontal cortex (0.674 ± 0.074 % ID/g tissue at 20 min post injection). Blood radioactivity concentrations were consistently low (a maximum value of 0.062 ± 0.014 % ID/g tissue was obtained at 20 min post injection). An average frontal cortex-to-cerebellum ratio of about 1.7 was obtained. In the Sprague-Dawley rat biodistribution studies, a rapid washout of radioactivity from the brain was observed. [123I]-3-I-CO was displaced from the 5-HT2A receptor by ketanserin: radioactivity concentration in the 5-HT2A rich areas of the brain decreased by 50 % after ketanserin displacement. Nevertheless, the residual radioactivity levels in cerebellum after ketanserin displacement remained high, especially compared to the results obtained with [123I]-R91150, and are probably caused by aspecific binding of the radioligand to brain tissues. No radiolabelled metabolites could be detected in the blood or brain of Sprague-Dawley rats. The influence of P-glycoprotein modulation with cyclosporin A on the brain uptake of [123I]-3-I-CO was also investigated. On average, a 67 % increase in [123I]-3-I-CO radioactivity concentration was observed throughout the brain after treatment of the animals with cyclosporin A. We can conclude from these results that [123I]-3-I-CO is at least a partial substrate for P-glycoprotein efflux, but the increase in brain radioactivity concentration after cyclosporin A treatment was not as large as the increase observed with [123I]-R91150 (chapter 3). Although cortical tissues could be visualized using pinhole μSPECT imaging with [123I]-3-ICO, aspecific binding of the radioligand was observed in the cerebellum, probably limiting its application as a serotonin 5-HT2A receptor tracer in humans. μSPECT imaging quality also did not improve after cyclosporin A pre-treatment of the animals. Although the initial rodent studies demonstrated promising brain uptake of the radioligand, it can be concluded that [123I]-3-I-CO probably has very limited potential as a 5-HT2A tracer for SPECT, due to high aspecific binding and rapid washout of the radioligand out of the brain. Also, compared to other clinically used brain tracers (for example [123I]-R91150), the specific ‘signal’ of [123I]-3-I-CO in brain is too limited for application as a tracer in brain receptor imaging studies.".
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