title: Evaluation of Z-(R,R)-IQNP for the potential imaging of m2 mAChR rich regions of the brain and heart.
abstract: Alterations in the function or density of the m2 muscarinic (mAChR) subtype have been postulated to play an important role in various dementias such as Alzheimer's disease. The ability to image and quantify the m2 mAChR subtype is of importance for a better understanding of the m2 subtype function in various dementias. Z-(R)-1-Azabicyclo[2.2.2]oct-3-y (R)-alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (Z-(R,R)-IQNP) has demonstrated significant uptake in cerebral regions that contain a high concentration of m2 mAChR subtype in addition to heart tissue. The present study was undertaken to determine if the uptake of Z-(R,R)-IQNP in these regions is a receptor mediated process and to identify the radiospecies responsible for binding at the receptor site. A blocking study demonstrated cerebral and cardiac levels of activity were significantly reduced by pretreatment (2-3 mg/kg) of (R)-3-quinuclidinyl benzilate, dexetimide and scopolamine, established muscarinic antagonists. A direct comparison of the cerebral and cardiac uptake of [I-125]-Z-(R,R)-IQNP and [I-131]-E-(R,R)-IQNP (high uptake in ml, m4 rich mAChR cerebral regions) demonstrated Z-(R,R)-IQNP localized to a higher degree in cerebral and cardiac regions containing a high concentration of the m2 mAChR subtype as directly compared to E-(R,R)-IQNP. In addition, a study utilizing [I-123]-Z-(R,R)-IQNP, [I-131]-iododexetimide and [I-125]-R-3-quinuclidinyl S-4-iodobenzilate, Z-(R,R)-IQNP demonstrated significantly higher uptake and longer residence time in those regions which contain a high concentration of the m2 receptor subtype. Folch extraction of global brain and heart tissue at various times post injection of [I-125]-Z-(R,R)-IQNP demonstrated that approximately 80% of the activity was extracted in the lipid soluble fraction and identified as the parent ligand by TLC and HPLC analysis. These results demonstrate Z-(R,R)-IQNP has significant uptake, long residence time and high stability in cerebral and cardiac tissues containing high levels of the m2 mAChR subtype. These combined results strongly suggest that Z-(R,R)-IQNP is an attractive ligand for the in vivo imaging and evaluation of m2 rich cerebral and cardiac regions by SPECT.
authors.affiliation: Nuclear Medicine Group, Life Sciences Division, Oak Ridge National Laboratory, TN 37831-6229, USA. phm@ornl.gov
authors.forename: D W
authors.initials: DW
authors.lastname: McPherson
authors.forename: M
authors.initials: M
authors.lastname: Greenbaum
authors.forename: H
authors.initials: H
authors.lastname: Luo
authors.forename: A L
authors.initials: AL
authors.lastname: Beets
authors.forename: F F
authors.initials: FF
authors.lastname: Knapp
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D005069:Evaluation Studies as Topic; D005260:Female; D009206:Myocardium / Q000378:metabolism*; D011812:Quinuclidines / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000378:metabolism*; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D011812:Quinuclidines; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; C080526:1-azabicyclo(2.2.2)oct-3-yl 2-hydroxy-2-(1-iodo-1-propen-3-yl)-2-phenylacetate