IN-VIVO MAPPING OF CHOLINERGIC NEURONS IN THE HUMAN BRAIN USING SPECTAND IBVM

In the search for an in vivo marker of cholinergic neuronal integrity, we extended to human use the tracer (-)-5-[I-123]iodobenzovesamicol ( IBVM). Methods: IBVM, an analog of vesamicol that binds to the acetylc holine transporter on presynaptic vesicles, was prepared with specific activity greater than 1.11 x 10(9) MBq mmole(-1). After intravenous i njection of [I-123]IBVM, body distribution studies (n = 5) and brain S PECT studies (n = 5) were performed on normal human subjects (n = 10). SPECT images of the brain were collected sequentially over the first 4.5 hr following injection, and again 18 hr later. Data were realigned and transformed to stereotaxic coordinates, and localized activities were extracted for tracer kinetic analysis. The cerebral tracer input function was determined from metabolite-corrected radial arterial bloo d samples. The best data fit was obtained using a three-compartment mo del, including terms reflecting cerebral blood volume, exchange of fre e tracer between plasma and brain and specific binding. Results: Disso ciation of bound tracer was negligible for up to 4 hr. For the fitted parameters reflecting transport (K-1) and binding site density index ( k(3)), coefficients of variation were approximately 8% in cortical reg ions of interest. Relative distributions corresponded well with postmo rtem immunohistochemical values reported for the acetylcholine-synthes izing enzyme choline acetyltransferase, k(3) (IBVM binding site densit y index), and tracer activity distribution at 22 hr, but not at 4 hr a fter injection. Conclusion: SPECT imaging of [I-123]IBVM succeeds as a n in vivo measure of cholinergic neuronal integrity and should be usef ul for the study of cerebral degenerative processes such as Alzheimer' s disease.