Sur C, Hostetler E, Connolly BM, Miller PJ, O'Malley S, Chen T-, Culberson C, Harrison S, Mulhearn J, Zeng Z.
Pharmacological characterization of a novel fluorinated PET tracer for the detection of amyloid-s plaques.
Human Amyloid Imaging 2011 Meeting Abstracts. 2011 Jan 15;
Background: Amyloid-s (As) plaques have been successfully visualized in the brain of Alzheimer's disease (AD)
patients with PET tracers such as [11C]PIB. Yet, the short t1/2 of carbon-11 (20min) limits its use to clinical facilities
close to a cyclotron. In order to support multicenter clinical trials for novel AD therapies, the present work aimed
at developing a fluorine-18 (t1/2 110min) As PET tracer.
Methods: In vitro binding studies were performed on cortical homogenates from AD and aged-matched controls
with [3H]MK-3328, [3H]PIB and [3H]lazabemide. Autoradiographic mapping of [3H]MK-3328 binding site expression
was performed on AD brain sections and compared to the distribution of As plaques and astrocytes.
Results: [3H]MK-3328 binds to cortical As plaques with a Kd of 17}4 nM (n = 5) and a Bmax of 1600}419 nM (n = 5).
Screening against a diverse set of enzymes and receptors unexpectedly revealed an interaction between MK-
3328 and monoamine oxidase B (MAO-B). [3H]MK-3328 binds purified MAO-B with a Kd of 6}3 nM (n = 3). Specific
[3H]MK-3328 binding was also observed in non-AD human cortical membrane preparations and fully displaced by
MAO-B inhibitor lazabemide. Saturation studies in AD cortex demonstrated that MAO-B levels accounted for only
17}3% (n = 5) of As levels measured by [3H]PIB. [3H]MK-3328 autoradiography revealed a punctated expression
pattern in AD cortical areas comparable to [3H]PIB that was not blocked by lazabemide. Immunocytochemistry on
adjacent sections supported a close association between [3H]MK-3328 positive areas, As plaques labeled with
6E10 antibody and astrocytes stained with GFAP antibody.
Conclusions: Despite unanticipated MAO-B binding, these results indicate that MK-3328 has an in vitro
pharmacological profile supporting its development as a fluorine-18 PET tracer for the detection of As deposits in
AD patients. On going clinical studies will establish the value of this novel imaging agent for the detection of As
plaques in AD patients.