Human Imaging Studies Initiated with ORNL Agent for the Evaluation of the Muscarinic Acetylcholinergic Receptor Complex (August 1999)

In conjunction with collaborations in Finland and Sweden, initial clinical imaging studies with healthy volunteers have been initiated at the Karolinska Institute in Stockholm utilizing stereoisomers of iodine-123-labeled IQNP, a new ligand developed by Dr. D. W. McPherson and co-workers in the ORNL Nuclear Medicine Program in the Life Sciences Division. These new agents were developed to monitor changes which occur in the muscarinic receptor complex in various process such as aging, memory loss, alcoholism, in addition to dementia's such as Alzheimer's and Huntington's disease. These first human studies represent the culmination of several years of systematic evaluation in the design of improved agents. This research involved molecular modeling studies, development and optimization of new chemistry in which the stereoisomers of IQNP were prepared and evaluation in both in vitro and in vivo animal models.

From these detailed studies, the Z-(R,R)- and E-(R,R)-stereoisomers of IQNP were chosen as the best candidates for human studies. These imaging studies consisted of separately administering 5 mCi each of the E and Z-IQNP isomers independently to a volunteer in order to directly determine the binding of each isomer in the same individual by single photon computed tomographic (SPECT) imaging. From these initial studies the E-isomer was observed to accumulate in m1- rich areas while the Z-isomer accumulates to a higher degree in regions containing the m2 receptor. The results of these initial human studies confirm earlier data obtained from in vivo studies utilizing lower animals and primates and will serve as the basis for studies with iodine-123-labeled IQNP stereoisomers for evaluation in patients with various neurological deficits involving the muscarinic-cholinergic neuroreceptors. (Contact: Russ Knapp, 574-6225 or knappffjr@ornl.gov; Funding Source: KP)