In vivo metabolic studies of thetrans-(R,R) isomer of radioiodinated IQNP: A new ligand with high affinity for the M1 muscarinic-cholinergic receptor

Abstract

E-(R,R)-IQNP is a new ligand analogue of IQNB, which has high affinity for the cholinergic-muscarinic receptor. Earlier studies have demonstrated high cerebral uptake of activity with selective localization in M1 receptor subtype areas of the brain. In this paper we describe the results of metabolic studies of E-(R,R)-IQNP directed at determining the metabolic fate of this ligand and the identification of the radioactive species observed in the brain and heart tissue. Tissue Folch extracts demonstrated that the lipid-soluble extracts from brain contained 87.0% +/- 1.65% of the activity up to 24 h. In the heart, 61.9% +/- 7.50% of the activity was extracted in the lipid-soluble extract after 30 min, decreasing to 51.4% +/- 0.65% by 4 h. In contrast, data from other tissues studied demonstrated large amounts of either aqueous soluble activity or activity which was not extracted from the tissue pellet material; analysis of lipid organic extracts revealed the following results: liver (4 h), 7.43% +/- 0.96%; serum (4 h), 3.73% +/- 0.87%; urine (24 h), 9.4%; feces (24 h), 16.5%. Thin-layer chromatographic (TLC) and high-performance liquid chromatographic (HPLC) analyses of lipid-soluble brain extracts indicated that only unmetabolized E-(R,R)-IQNP was detected (99.4% +/- 1.25%). Activity which was extracted into the organic phase from heart tissue was also determined by TLC and HPLC analysis to contain large amounts of unmetabolized ligand after 4 h (88.5% +/- 0.57%). In addition, however, low levels of two additional radioactive components were detected which increased with time. TLC analysis of the plasma lipid extracts indicated only a small amount of unmetabolized E-(R,R)-IQNP.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure Elucidation Via Stereoselective Synthesis of the Acetate Center of 1-Azabicyclo[2.2.2]oct-3-yl α-Hydroxy- α-(1-iodo-1-propen-3-yl)-α-phenylacetate (IQNP). A High Affinity Muscarinic Imaging Agent for SPECT

“…IQNP has been shown to be readily radioiodinated, to cross the blood−brain barrier and to localize in regions of the brain which contain varying concentrations of the muscarinic acetylcholine receptor (mAChR) . In addition, the various stereoisomers of IQNP demonstrated modest selectivity for the various subtypes of mAChR. − …”