PURPOSE: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.PROCEDURES: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.CONCLUSION: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.

Butyrylcholinesterase (BuChE) is a serine hydrolase enzyme that, along with acetylcholinesterase (AChE), catalyzes the hydrolysis of acetylcholine. Increased levels of BuChE are observed in Alzheimer's disease brain especially in neuritic plaques and neurofibrillary tangles, characteristic of the disease. This makes BuChE a suitable target for disease-specific neuroimaging. Cholinesterase ligands currently being investigated for imaging have the radioisotope in that part of the molecule that is the initial leaving group in the enzyme catalyzed hydrolysis. This may be, in part, responsible for poorly defined images with these ligands. We propose that BuChE-specific radiopharmaceuticals, having the radioisotope in the part of the molecule that forms the ligand-enzyme intermediate, can be used in PET and SPECT imaging to detect this enzyme in vivo, and thus the neuritic plaques and neurofibrillary tangles associated with AD. Imaging the AD plaques and tangles may provide an early diagnosis as well as a method for treatment monitoring. Piperidinols and pyrrolidinols were reacted with various acid chlorides and isocyanates to produce corresponding esters and carbamates, respectively. These compounds were evaluated using enzyme kinetics for their affinity towards both BuChE and AChE. BuChE-specific ligands were then transformed into intermediates suitable for incorporation of a radiolabel, either 123I for SPECT or 18F for PET imaging. Carrier free radiolabeled ligands were then administered to experimental animals and the distribution of BuChE in vivo determined. Several piperidinols and pyrrolidinols proved to be specific ligands for BuChE. These ligands were successfully transformed into both tin and tosylate intermediates. 123I was successfully incorporated into these molecules. Preliminary animal imaging indicated regional distribution of ligands. BuChE has been previously demonstrated to be involved in the pathology of AD. We have synthesized several BuChE-specific ligands that have been successfully radiolabeled. Preliminary animal imaging with these ligands indicated that there is regional distribution in the body and that these ligands are taken up into the brain. Further refinement of imaging methodology is underway. The imaging of BuChE in vivo may facilitate early diagnosis and treatment monitoring of AD.

TO THE EDITOR: Corticobasal degeneration (CBD) is a slowly progressive disorder, characterized by initially unilateral akinesia, rigidity, apraxia, cortical sensory impairment, postural instability, and the alien hand syndrome.1–3 The diagnosis can be challenging, given the variable presentations that reflect which brain region is affected first. Neuropathology is said to provide a definitive diagnosis, with neuronal achromasia and cortical atrophy of the frontoparietal region.1,3 SPECT can show asymmetrical parietal hypoperfusion,2,4,5 and focal atrophy can be seen on MRI.