Evaluation of Z-(R,R)-IQNP for the potential imaging of m2 mAChR rich regions of the brain and heart

Alterations in the function or density of the m2 muscarinic (mAChR) subtype have been postulated to play an important role in various dementias such a s Alzheimer's disease. The ability to image and quantify the m2 mAChR subty pe is of importance for a better understanding of the m2 subtype function i n various dementias. Z-(R)-1-Azabicyclo[2.2.2]oct-3-y (R)-alpha-hydroxy-alp ha-(1-iodo-1-propen-3 -yl)-alpha-phenylacetate (Z-(R,R)-IQNP) has demonstra ted significant uptake in cerebral regions that contain a high concentratio n of m2 mAChR subtype in addition to heart tissue. The present study was un dertaken to determine if the uptake of Z-(R,R)-IQNP in these regions is a r eceptor mediated process and to identify the radiospecies responsible for b inding at the receptor site. A blocking study demonstrated cerebral and. ca rdiac levels of activity were significantly reduced by pretreatment (2-3 mg /kg) of (R)-3-quinuclidinyl benzilate, dexetimide and scopolamine, establis hed 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 m1 , m4 rich mAChR cerebral regions) demonstrated Z-(R,R)-IQNP localized to a higher degree in cerebral and cardiac regions containing a high concentrati on of the m2 mAChR subtype as directly compared to E-(R,R)-IQNP. In additio n, 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 significan tly 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 t he lipid soluble fraction and identified as the parent ligand by TLC and HP LC analysis. These results demonstrate Z-(R,R)-IQNP has significant uptake, long residence time and high stability in cerebral and cardiac tissues con taining high levels of the m2 mAChR subtype. These combined results strongl y 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.