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Characterization of [11C]McN5652 in various animal species: Implications for tracer development
Brust, P.; Zessin, J.; Kretzschmar, M.; Bergmann, R.; Friedrich, A.; Füchtner, F.; Hinz, R.; Steinbach, J.; Johannsen, B.;
Loss of 5-HT transporter (SERT) sites has been implicated in various brain diseases. Therefore, the development of suitable radioligands for neuroimaging of the SERT in the human brain is important. [11C](+)McN5652 is the only PET radioligand which is available for clinical use. However this compound is not optimal because of its rather slow kinetics and high non-specific binding in the human brain. For the evaluation of further radioligands in animal experiments a comparison with [11C](+)McN5652 is recommendable. Therefore we have studied the binding and distribution of [11C](+)McN5652 in various animal species.

The in vitro binding of [11C](+)McN5652 was studied on tissue homogenates and slices of rat and porcine brain and on the SERT expressing human placental cell line JAR. The in vivo binding of [11C](+)McN5652 was investigated in rats, mice and pigs. 35 Wistar rats (age: 8 weeks) were injected with 20 MBq [11C](+)McN5652 and sacrificed at 5, 30, 60, or 90 min p.i. 11 rats were treated additionally with 5 mg/kg i.v. fluoxetine or citalopram 5 min before tracer injection. Additionally 6 mice were injected with 80-200 MBq [11C](+)McN5652 and sacrificed at 60 min p.i. The brains were quickly removed and frozen for autoradiography. Three six weeks old farm-bred female pigs were studied with PET (31 frames, 120 min) under general anesthesia (0.5-0.75% isoflurane in N2O/O2. 46-48 arterial blood samples were obtained at defined time points. Additional arterial samples were withdrawn for detection of metabolites using thin-layer chromatography.

Evidence for a significant binding of [11C](+)McN5652 not only to SERT but also to the norepinephrine (NET) and dopamine transporters (DAT) was found in vitro. IC50 values of 6.6 and 9.4 nM for NET and DAT were measured. Binding equilibrium at JAR cells was reached after about 60 min. Nonspecific binding (defined by 10 µM citalopram) was 76%. In rats a high brain uptake was found with the highest values measured in thalamus, colliculi and olfactory bulb (~1.3 % g-1). Only in these regions a significant inhibition (38-48%) by fluoxetine and citalopram was found. Similar results were obtained by autoradiography in mice. Also the PET data obtained in pigs revealed a high blood-brain transfer of [11C](+)McN5652 (K1: 0.22-0.43 ml g-1 min-1). Rapid metabolism was observed. More than 50% metabolites were found at 12 min p.i. Significant binding of [11C](+)McN5652 was observed in all 23 regions studied (k3: 0.018-0.044 min-1). The highest binding potential was found in thalamus and colliculi. Preinjection of citalopram or fluoxetine reduced k3 by 30-70%.

A high consistency exists between the in vitro and in vivo studies in various animal species. The data reveal a displaceable binding in target regions but also a rather high nonspecific binding of [11C](+)McN5652. Binding to other targets such as NET and DAT may contribute to this. The location of serotonin uptake sites in the porcine brain appears to be similar to that found in rats and mice which makes pigs a suitable animal model for the development of radioligands for studying serotonergic functions with PET.
  • Abstract in refereed journal
    NeuroImage Vol. 11 (6Pt2) (2000) S66
  • Lecture (Conference)
    Third International Symposium on Functional Neuroreceptor Mapping, New York, 09.-11.06.2000

Publ.-Id: 3488 - Permalink