Evaluation of 18F-AV-1451 kinetic modeling in patients in Alzheimer's disease and healthy controls

Molecular imaging biomarkers have the potential to aid in the diagnosis of
patients with cognitive impairment, who are being evaluated for Alzheimer*s
disease (AD) (Dubois, 2010; McKhann, 2011). Positron emission tomography (PET)
ligands such as florbetapir F 18 (Wong, 2010) may provide a minimally invasive
estimate of cortical beta amyloid (A*) neuritic plaque deposition, a hallmark
pathology, and a required element for the evaluation of AD
neuropathologicdiagnosis (Hyman 2012).
In contrast to A* neuritic plaques, the density and distribution of
phosphorylated tau, aggregated in neurofibrillary tangles, increases with
AD-related cognitive impairment and correlates with neurodegeneration (Dickson
et al., 1997; Duyckaerts et a., 1987). Thus, a PET imaging agent that binds to
phosphorylated tau has potential application as a biomarker for disease
severity/neurodegeneration and may be useful both for selecting patients for
therapy and for monitoring disease progression in therapeutic trials.
18F-AV-1451(originally named [F-18]T807 by Siemens Molecular Imaging Biomarker
Research group) has been developed as a positron emitting radiopharmaceutical
for in vivo imaging of tau protein aggregates (Xia et al., 2013).
Autoradiography results using tissue sections from human brains showed a strong
signal in the grey matter of cortical slices from tau positive brains, but weak
or no binding in tau negative, A* positive, or tau and Ab negative
tissue.Scatchard analysis based on this heterogeneous autoradiography assay
yielded an estimated Kd of 15nM. A saturation binding experiment using purified
Paired Helical Fragment Tau isolated brains of AD patientsyielded a Kd value of
0.7 nM.
AV-1451 was assessed in competitive binding assays against a panel of 72 of the
most common central nervous system (CNS) targets and no clinically relevant
inhibition was seen.AV-1451 was positive in the in vitro hERG assay, albeit at
a concentration at least 50 fold greater than the maximum theoretical plasma
concentration; in vivo cardiovascular safety pharmacology assessments in
dogsshowed no evidence of QT prolongation at doses up to 50x the intended
maximum human dose (MHD). Nonetheless, until sufficient human cardiovascular
safety data are available, initial clinical studies will exclude subjects with
a history of risk factors for Torsades de Pointes and subjects taking drugs
known to prolong the QT interval.
In vivo safety pharmacology studies were also conducted in rats to determine
potential effects on the CNS and respiratory systems. In these studies no
clinically relevant effects were reported at doses exceeding 100x the intended
MHD. Additionally, non-radioactive AV-1451 has been tested in single and
repeat-dose toxicology studies in rat and dog. In each of these studies the no
observable adverse effect levels (NOAELs) were the highest doses tested (150x
MHD for single, 50x MHD for repeat).
Potential genotoxicity of non-radioactive AV-1451 was tested in both in vitro
and in vivo assays. In the in vitro assays, AV-1451 tested positive for
potential genotoxicity. However, in the in vivo rat micronucleus assay, at
doses up to 750x MHD (scaled allometrically), AV-1451 showed no evidence of
genotoxicity. The different results in the in vitrogenotoxicity assays and the
in vivo micronucleus study are likely related to differences in the exposure
conditions encountered by the target cells in the different test systems. In
vivo, AV-1451 is cleared rapidly; however, the in vitro experiments employ
static, prolonged exposure of cells to high concentrations of the test article.
While the in vitro data show the potential for genotoxicity, the in vivo data
provide assurance that genotoxicity is unlikely to occur at clinically-relevant
doses for human diagnostic studies.
18F-AV-1451 has been evaluated in two human studies under the exploratory IND
(Chien, et al., 2013). Adverse events reported have been mild and transient;
none have been considered related to 18F-AV-1451 administration.Preliminary
evaluation of the PET images suggest that 18F-AV-1451 is eliminated from normal
brain yielding only a diffuse pattern of background activity (Figure 1),
whereas a regionally-specific gray matter distribution is observed in subjects
with high probability AD (Figure 2).

The primary objectives of this study are:
* To evaluate tracer kinetic models for the purpose of quantifying specific
binding of 18F-AV-1451 in cross sectional and longitudinal applications; and
* To evaluate simplified methods for quantification of 18F-AV-1451 uptake.

This study will evaluate18F-AV-1451 kinetic modelling in patients with
Alzheimer*s disease and in cognitively normal healthy controls. Subjects will
be split into 2 cohorts: cohort 1 will include approximately 5 probable AD
subjects and 5 age-matched cognitively healthy volunteer subjects. Subjects in
cohort 1 will receive a18F-AV-1451 PET scan at baseline and again at
approximately one year later. Cohort 2 will include approximately 5 subjects
with probable AD and 5 age-matched cognitively healthy volunteer subjects.
Subjects enrolled in cohort 2 will receive a single 18F-AV-1451 PET scan. All
AD patients will be screened according to the standardized clinical dementia
screening performed at VUMCand subjects will provide informed consent before
starting any study procedures. If MRI brain has been performed more than 6
months (for AD patients) or 12 months (for healthy controls) before baseline
imaging, MRI brain will be repeated.
All subjects will receive a venous and arterial cannula.Approximately 240 MBq
of18F-AV-1451will be injected intravenously (IV) as a bolus. Immediately
following injection, a dynamic 60 minute PET scan will be performed. At
approximately 80 minutes post injection, an additional dynamic PET scan will
occur for 50 minutes. No more than 500cc of blood will be withdrawn. Arterial
blood will be withdrawn continuously from 0-60 minutes using an online
detection system which will be cross-calibrated against the PET scanner. At set
times, additional manual blood samples will be taken to measure whole blood and
plasma concentrations. In addition, plasma samples will be used to determine
parent 18F-AV-1451fractions.
Approximately one year following the baseline scan, cohort 1 subjects will
return to the clinic for a second18F-AV-1451 PET scan. Subjects will undergo
the same procedures as the baseline PET visit including arterial blood draws
and blood sampling to measure whole blood and plasma concentrations.
Following each 18F-AV-1451 PET visit, a follow-up phone call to the subject, or
designated decision maker, will be conducted between 2 or 3 business days of
the imaging day,

Name of compound: 18F-AV-1451(also known as [F-18]T807)
Dose: 240 MBq (6.5mCi)
Route of Administration: Intravenous (IV) bolus

Risks associated with participation in this study are related to 1) radiation
exposure; 2) idiosyncratic reaction to the tracer; 3) placement of the arterial
and intra-venous catheter; and 4) discomfort during PET scanning.