[PETDE10] Imaging of phosphodiesterase 10 A (PDE10A) enzyme levels in the living human brain of Huntington*s disease gene expansion carriers and healthy controls with positron emission tomography

Huntington*s disease (HD) is a neurodegenerative disorder characterised by
progressive loss of the medium-sized spiny neurons in the striatum and by the
development of chorea, psychiatric symptoms and cognitive deficits. The
hallmark of the disease is the accumulation of aggregates of mutated
huntingtin, which has been found to impair cyclic adenosine monophosphate
(cAMP) signaling and gene transcription mediated by the cAMP responsive-element
binding protein (CREB). Phosphodiesterase 10 A (PDE10A) is an enzyme which is
highly enriched in the mediumsized spiny neurons of the striatum and has an
important role in the regulation of cAMP and cyclic guanosine monophosphate
(cGMP) levels. Targets genes of CREB include those responsible for
neurotransmitter synthesis, release and signaling pathways, and also the brain
derived nerve factor. Inhibition of PDE10A by inhibitors such as TP10 has been
found to decrease neurodegenerative changes in the striatum of animal model of
HD and restore cAMP dependent CREB signaling.
Preliminary data in human subjects suggest that [18F]MNI-659 is a suitable
radioligand for imaging PDE10A in vivo.

The primary objective is to measure the availability of the PDE10A enzyme in
Huntington*s Disease (HD)gene expansion carriers (HDGECs) by estimating and
comparing the distribution volume (VT) of the radioligand [18F]MNI-659 in the
striatum (caudate and putamen), globus pallidus, ventral striatum including
nucleus accumbens, thalamus, cortex and cerebellum in HDGECs and age (± 5
years)- and gender-matched healthy controls (HCs).
The secondary objectives are:
1) To compare the non-displaceable distribution volume (VND) of [18F]MNI-659 in
the cerebellum between HDGECs and HCs. If no differences in the VND will be
found, the cerebellum will be considered as reference region and the binding
potential (BPND) will be estimated as: (VT-VND)/VND and with the simplified
reference tissue model SRTM and with the non-invasive Logan graphical analysis.
2) To compare the kinetics, metabolism and the protein binding of the
[18F]MNI-659 in HDGECS and HCs.
3) To compare the availability of the PDE10A enzyme in sub-divisions of the
striatum (caudate, putamen and ventral striatum including nucleus accumbens)
with the D2 receptor availability in the same regions in HDGECs and HCs.
4) To explore the correlation between the availability of the PDE10A enzyme (VT
or BPND) and the number of CAG repeats in HDGECs.
5) To explore the correlation between the availability of the PDE10A enzyme (VT
or BPND) in HDGECs and disease duration (the classical definition of time when
motor clinical manifestation first became noticeable will be used), clinical
ratings (stage and Unified Huntington*s Disease Rating Scale [UHDRS]),
functional assessments (Total Motor Score [TMS] and Total Functional Capacity
[TFC]) and psychiatric and cognitive assessments (Cognitive Battery Assessment
[CBA]).

The aim of this study is to measure the availability of the PDE10A enzyme in
HDGECS using the recently developed radioligand [18F]MNI-659. The study will be
cross-sectional, examining HDGECs at different stages of the disease
(pre-manifest, stage 1 and stage 2), in comparison with HCs, matched by age and
gender. The HDGECs included in this study will be recruited from the large
database of the REGISTRY or ENROLL-HD studies. The study will have an adaptive
design, consisting of the following steps:
1a) Inclusion of 4 HCs in the first cohort to confirm quantification,
metabolism, and protein binding of [18F]MNI-659. These 4 HCs will be recruited
based on the demographics (age and gender) provided by European
Huntington-Disease Network (EHDN) for the first cohort of stage 1 HDGECs to be
included.
1b) Inclusion of 5 stage 1 HDGECs and 1 additional HC (matched by age and
gender) in the first cohort to measure the availability of the PDE10A enzyme.
2) Inclusion of approximately 10 HDGECs and an equal number of HCs (matched by
age and gender) in the second cohort. The HDGECs will be either:
a) Pre-manifest HDGECs, if PDE10A levels (VT) are decreased by more than 40% in
the first cohort of stage 1 HDGECS.
b) Additional stage 1 HDGECS, if PDE10A levels (VT) are decreased by between 30
and 40% in the first cohort of stage 1 HDGECs. In addition, approximately 5
additional stage 2 HDGECs may be recruited within this cohort or
c) Stage 2 HDGECs, if PDE10A levels (VT) are decreased by less than 30% in the
first cohort of stage 1 HDGECs.
3) Inclusion of additional HDGECs and HCs (matched by age and gender) to
provide further sample size to explore the correlation between PDE10A level (VT
or BPND) and clinical measures and between PDE10A levels (VT) and CAG repeats.

In the study, comprising all steps, there will be approximately 45 HDGECs and
an equal number of HCs.


The HDGECS will perform 5 study visits (screening, screening telephone
follow-up, Magnetic Resonance Imaging (MRI), Positron Emission Tomography (PET)
and telephone follow-up) during a maximum of 97 days.
The healthy controls will perform 4 study visits (screening, MRI, PET and
telephone follow-up) during a maximum of 97 days.

Interim data analyses will be performed after steps 1a, 1b and 2 and the
results will be evaluated by an Interim Review Committee (ICR). The committee
will decide whether to continue or stop the study and will also decide the
additional number of HDGECs of each HD stage to be included in the study.

The radioligands [11C]raclopride and [18F]MNI-659 will be administered at doses
less than 10 micrograms, within the micro dosing concept, and no
pharmacological effects are expected. [11C]raclopride is a well-established
radioligand for the dopamine D2 receptors that was developed at the Karolinska
Institute (KI) in the 1980s and is the PET radioligand most widely used
worldwide. No safety issues have ever been reported. [18F]MNI-659 has been
administered to 9 healthy volunteers at the Molecular Neuroimaging Center, New
Haven, CT, USA, without any safety concern.
The injected radioactivity of [11C]raclopride will be 300 MBq/70 kg of body
weight ±10% and of [18F]MNI-659 it will be 185 MBq/70 kg of body weight ±10%.
The effective dose for the injection of [11C]Raclopride + [18F]MNI-659 is 8 mSv
(2 years of background radiation in Stockholm).
Though PET imaging itself causes no pain there may be some discomfort from
having to remain still during the scanning. Claustrophobic subjects may feel
some anxiety while being scanned.
Arterial blood sampling will be performed for the PET measurements done with
[18F]MNI-659 to derive the input function for the compartmental analysis. A
total of approximately 110 mL blood will be drawn. Arterial cannulation will be
performed by a neuro-anaesthesiolgist under local anaesthesia. Arterial
cannulation can be associated with a formation of a haematoma. To prevent or
reduce haematoma, a local compression for approximately 20 min will be made on
the site of cannulation at the end of the PET measurements.
No specific benefits for the HCs in the current study are foreseen except for
the medical screening. Subject remuneration will be paid to each participating
HC after study completion. The remuneration covers loss of time and any
inconvenience caused by study participation.
The HDGECs will be compensated for their travel expenses. They will receive no
immediate benefit from participating in the study, the only potential benefit
is a better understanding of HD and the possibility that the information
obtained in this study will lead to potential treatments in the future.