Synthesis and preliminary evaluation of piperidinyl and pyrrolidinyl iodobenzoates as imaging agents for butyrylcholinesterase.
OBJECTIVE
The purpose of this study is to synthesize and evaluate specific agents for molecular imaging of butyrylcholinesterase (BuChE), known to be associated with neuritic plaques and neurofibrillary tangles in Alzheimer's disease (AD). In this study, these agents were tested in a normal rat model. The distribution of radiolabel was compared with known BuChE histochemical distribution in the rat brain.


METHODS
Iodobenzoate esters were synthesized and tested, through spectrophotometric analysis, as specific substrates for BuChE. These compounds were converted to the corresponding (123)I esters from tributyltin intermediates and purified for studies in the rat model. Whole body dynamic scintigraphic images were obtained for biodistribution studies. Autoradiograms of brain sections were obtained and compared to histochemical distribution of the enzyme in this model system.


RESULTS
The three iodobenzoate esters studied were specific substrates for BuChE. Whole body biodistribution studies with (123)I-labeled compounds showed rapid disappearance from the body while radioactivity was retained in the head region. Brain section autoradiography of animals injected with these labeled compounds indicated that most areas known to contain BuChE corresponded to areas of radioactivity accumulation.


CONCLUSIONS
BuChE-specific radiolabeled iodobenzoates enter the brain and, in general, label areas known to exhibit BuChE activity in histochemical studies. Such molecules may represent a new direction for the development of agents for the molecular imaging of BuChE in the living brain, especially in regions where BuChE-containing neuropathological structures appear in AD.
Department of Anatomy and Neurobiology, Dalhousie University, Halifax, NS, Canada.
Ian R
IR
Macdonald
G Andrew
GA
Reid
E Eric
EE
Joy
Ian R
IR
Pottie
Gilbert
G
Matte
Steven
S
Burrell
George
G
Mawko
Earl
E
Martin
Sultan
S
Darvesh
D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology; D000682:Amyloid / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002091:Butyrylcholinesterase / Q000378:metabolism*; D005069:Evaluation Studies as Topic; D007150:Immunohistochemistry; D007457:Iodine Radioisotopes; D007463:Iodobenzoates / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D008024:Ligands; D008297:Male; D008968:Molecular Conformation; D057054:Molecular Imaging / Q000379:methods*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014220:Trialkyltin Compounds / Q000737:chemistry
D000682:Amyloid; D007457:Iodine Radioisotopes; D007463:Iodobenzoates; D008024:Ligands; D010880:Piperidines; D011759:Pyrrolidines; D014220:Trialkyltin Compounds; C011559:tributyltin; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase