SYNTHESIS OF (R,S)-TRANS-8-HYDROXY-2-[N-N-PROPYL-N-(3'-IODO-2'-PROPENYL)AMINO]TETRALIN (TRANS-8-OH-PIPAT) - A NEW 5-HT(1A) RECEPTOR-LIGAND

In order to develop tracers with higher specific activity to supplant the currently used [H-3]-8-OH-DPAT [8-hydroxy-2-(N,N-di-n-propylamino)tetralin] for in vitro and in vivo evaluation of 5-HT1A receptors, a new radioiodinated ligand was prepared. (R,S)-trans-8-Hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)amino]tetralin (trans-8-OH-PIPAT), 8, was synthesized by a 10-step reaction. Binding studies with rat hippocampal membrane homogenates showed that 8 exhibited a K(i) value of 0.92 nM against (R,S)-[H-3]-8-OH-DPAT. Radiolabeled[I-125]-8 was prepared from the corresponding tri-n-butyltin precursor via an oxidative iododestannylation reaction with sodium [I-125]iodide. Binding studies in the hippocampal homogenates revealed that [I-125]-8 bound to a single high-affinity site (K(d) = 0.38 +/- 0.03 nM, B(max) = 310 +/- 20 fmol/mg of protein). Competition binding experiments clearly indicated that the new ligand displayed the expected 5-HT1A receptor binding profile. The rank order of potency was (R,S)-trans-8-OH-PIPAT > (R,S)-8-OH-DPAT > WB4101 > 5-HT > (R,S)-trans-7-OH-PIPAT > (R,S)-7-OH-DPAT > (R,S)-propranolol > spiperone >> ketanserin >> dopamine > atropine. This new ligand offers several unique advantages, including high specific activity, high binding affinity, and low nonspecific binding, all of which make it an excellent probe for the investigation and characterization of 5-HT1A receptors.