[125/123I]IPH: A radioiodinated analog of epibatidine for in vivo studies of nicotinic acetylcholine receptors

Tomographic imaging of central nicotinic acetylcholine receptors (nAChRs) via single photon emission computed tomography (SPECT) has been hampered by the lack of a radioligand with suitable in vivo binding characteristics. Therefore, a novel analog of epibatidine, (±)-exo-2-(2-iodo-5-pyridyl)-7-azabicyclo[2.2.1]heptane (IPH), labeled with [¹²⁵I] or [¹²³I] was evaluated as an in vivo marker of central nicotinic acetylcholine receptors (nAChRs). [¹²⁵I]IPH showed substantial brain penetration (4.2% of the injected dose at 30 min) and a cerebral biodistribution in mice consistent with the in vivo labeling of nAChRs (% injected dose/gram of thalamus, superior colliculi ≫ cerebellum). [¹²⁵I]IPH binding sites were shown to be saturable with unlabeled IPH (ED₅₀ approximately 1 μg/kg). The uptake of [¹²⁵I]IPH was blocked significantly by the nicotinic agonists, cytisine, lobeline, and (−)-nicotine, but not by the noncompetitive nAChR antagonist, mecamylamine. Antagonists of muscarinic (scopolamine), serotonin (ketanserin), and opioid (naloxone) receptors had no significant effect on [¹²⁵I]IPH binding. A preliminary SPECT imaging study with [¹²³I]IPH in a baboon showed [¹²³I]IPH to localize in nAChR-rich areas of brain (thalamus > frontal cortex > cerebellum). [¹²³I]IPH binding in baboon brain was also displaced (35–45% displacement) by a challenge dose of cytisine showing that a well-characterized nicotinic agonist effectively competes for [¹²³I]IPH binding sites. [¹²³I]IPH seems well suited for imaging studies of nAChRs and, to our knowledge, is the first SPECT agent that has allowed for the visualization of nAChRs in primate brain. Synapse 26:392–399, 1997. © 1997 Wiley-Liss Inc.