2-[¹²⁵Iodo]LSD, a new ligand for the characterisation and localisation of 5-HT₂ receptors

Summary

• 1. LSD was iodinated with Na¹²⁵I and chloramine T, to get the radioligand [¹²⁵I]LSD (¹²⁵IOL) and with N-I-succinimide to obtain the nonradioactive compound 2-I-LSD (IOL) for comparative pharmacological studies.

• 2. The introduction of iodine in position 2 of LSD leads to an increase in selectivity for 5HT₂ receptors. In rat cortex membranes, ¹²⁵IOL possesses a K _D=0.9±0.1 nmol/l, B _max=240±20 fmoles/mg, and a nonspecific binding of 30–40% in presence of 100 nmol/l ketanserin.

• 3. In competition experiments, 5HT antagonists showed monophasic displacement curves. Their K _I-values correlate well with pD′₂-values for inhibition of 5HT-induced contraction of canine basilar artery. It can be concluded that the sites labelled by ¹²⁵IOL have pharmacological properties in common with central 5HT₂ receptors, which are identical with vascular postjunctional 5HT receptors.

• 4. The high specific radioactivity of ¹²⁵IOL permits detection of even small 5HT₂ receptor densities which exist in the guinea pig ileum. These ¹²⁵IOL binding sites are pharmacologically different to those found in the brain or on the vessels and might be a special subpopulation of 5HT₂ sites. For example, ketanserin has a high affinity to the sites labelled by ¹²⁵IOL in the brain and a 100 times lower affinity to the sites labelled in the ileum.

• 5. In a routine binding screen with various ligands, the inhibition constants of IOL for α₁, α₂, β, histamine and muscarinic receptors are >100 nmol/l with the exception for dopamine receptors, 40 nmol/l.

• 6. ¹²⁵IOL was employed for the autoradiographic localisation of its binding sites after in vitro labelling of microtome rat brain sections. ¹²⁵IOL labelled 5HT₂ sites in the cortex and dopamine receptors in the nucleus caudatus. The exposure times required were very short, compared to those of other 5HT₂ ligands available.