Design and Biological Evaluation of Technetium(V) Complexes for Serotonin-5-HT2A Receptor Binding


Design and Biological Evaluation of Technetium(V) Complexes for Serotonin-5-HT2A Receptor Binding

Pietzsch, H.-J.; Scheunemann, M.; Kretzschmar, M.; Seifert, S.; Syhre, R.; Johannsen, B.

Starting from the lead structure of ketanserin, a prototypic serotonin (5-HT) antagonist, a series of oxotechnetium(V) complexes were synthesized which are able to compete with [3H]ketanserin in receptor binding assays.
In order to imitate organic 5-HT2 receptor ligands, fragments of ketanserin were combined with chelate moieties. Lipophilic complexes, consisting of a small S4 or S3N thiolate/thioether chelate unit, protonable nitrogen containing spacer and benzyl moiety significantly inhibited the specific binding of [3H]ketanserin with IC50 values between 10 and 50 nM.
Low brain uptake is a generally accepted problem in developing 99mTc brain receptor imaging agents. For some representatives of 5-HT2A receptor binding agents it was tried to improve the original low brain uptake of 0.4 % ID in rats 5 min p.i. by modifying the lipophilic properties of the molecules. Because of the presence of a protonable nitrogen, which according to the pK value leads to ionization of the molecule at blood pH, the pK value was considered to be the parameter most suitable for adjustment of lipophilicity. Insertion of ether-oxygen in the molecule of 5 candidates lowers the apparent pK value from 10.0 to 8.3 and dramatically increases the brain uptake up to 1.3 % ID at 5 min.
Finally, the synthesis and in vitro autoradiography of a novel Tc-99m ligand with subnanomolar affinity to the 5-HT2A receptor is reported. The complex combines the 4-(4-fluoro)-benzoyl piperidine portion derived from ketanserin with a neutral oxotechnetium(V) chelate in form of a mixed ligand "3+1" unit containing the SNS/S donor set. The analogous 99Tc compound has been synthesized as a surrogate for the Tc-99m complex for use in receptor binding assays and for complete structural characterization.
In competition experiments the Tc-99 complex as well as its Re analogue display subnanomolar affinity towards the 5-HT2A receptor (Ki 0.44 nM for Tc, 0.25 nM for Re).
In vitro autoradiographic studies clearly indicate the accumulation of the Tc-99m compound in 5-HT2A receptor rich areas of the brain. This enrichment can be blocked by 5-HT2A receptor antagonists such as mianserin and ketanserin and is therefore specific.

  • Contribution to external collection
    IAEA Technical Document (IAEA TECDOC)
  • Lecture (Conference)
    IAEA Research Coordination Meeting on CNS Receptors, Montevideo/Uruguay, 24.-28.04.2000

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Publ.-Id: 3346