Positron Emission Tomography (PET) is a functional imaging technique, which enables in vivo visualization of biological molecules expressed in human tissues. Brain PET is most powerful to study a vast range of neurological and psychiatric disorders in vivo, targeting neuronal and glial activity, metabolism, cerebral blood flow, receptor proteins or misfolded proteins.

In vivo imaging of synaptic density in the human brain has become feasible through development of [11C]UCB-J, a PET radioligand for the synaptic vesicle protein SV2A, which is ubiquitously and homogeneously present in presynaptic terminals throughout the brain. A first study in Huntington's disease (HD) mutation carriers showed loss of striatal [11C]UCB-J binding (also when corrected for atrophy), as well as in the neocortex (Delva et al, Neurology 2022). Moreover, regional synaptic loss was highly correlated to motor impairment.

In order to be able to use SV2A PET as widespread available biomarker tool to assess synaptic integrity, disease progression and/or response to mHTT lowering drugs, the short half-life of 11C (20 minutes) for [11C]UCB-J remains a hurdle. Recently, [18F]SynVesT-1, an optimized 18F-labeled analogue of [11C]UCB-J with similar kinetics, binding affinity, and test-retest precision properties has been evaluated in humans.

However, there is evidence from preclinical studies conducted at University of Antwerp that in the zQ175DN knock-in mouse model of HD, larger variability and lower effect-sizes are seen with [18F]SynVest-1 than with [11C]UCB-J.

In order to ascertain a similar effect size and quantification properties for [18F]SynVest-1 and [11C]UCB-J PET in human HD patients and to validate simplified measures (such as SUVR with white matter as reference region) and SynVest, this head-to-head fully quantitative study is performed.

Inclusion Criteria:

1. Healthy controls (n = 10-20)

   • Subject is judged to be in good health by the investigator on the basis of medical history, physical examination including vital signs, clinical laboratory test and urinalysis.
   • No history or evidence of current major neurological, internal or psychiatric disorder, based on the medical assessment as described hereabove and neuropsychological assessment.
   • In subjects < 60 years of age, an unremarkable structural MRI scan as assessed by expert radiologist. In subjects >= 60 years of age white matter hyperintensities corresponding to a white matter lesion (WML) Fazekas score < 2 on the Age-Related White Matter changes scale are acceptable.

2. HD-ISS stage 3 HD mutation carriers (n = 10)

   • HTT CAG repeat expansion 40 - 50
   • stage 3 as determined by the HD-ISS staging criteria
   • UHDRS TFC >/= 10

3. HD-ISS stage 2 HD mutation carriers (n = 10)

   • HTT CAG repeat expansion 40 - 50
   • stage 2 as determined by the HD-ISS staging criteria
   • PIN score 0.47 - 1.84

Exclusion Criteria:

• Neuropsychiatric diseases; for HD mutation carriers any neuropsychiatric diseases other than HD
• Major internal medical diseases
• White matter lesion load on FLAIR Fazekas score 2 or higher or other relevant MRI abnormalities
• History of alcohol abuse or current alcohol abuse (chronic use of more than 15 units per week) or drug use
• Contraindications for MR
• Subject suffers from claustrophobia or cannot tolerate confinement during PET-MRI scanning procedures; subject cannot lie still for 30 minutes inside the scanner.
• Subject is unwilling to avoid unusual, unaccustomed, or strenuous physical activity (i.e., weightlifting, running, bicycling) from the time of the pre-study visit until the end of scanning.
• Subject does not understand the study procedures or does not have a guardian who understands the study procedures.
• Subject (or guardian) is unwilling or unable to perform all of the study procedures or is considered unsuitable in any way by the principal investigator.
• Subject is on anticoagulant therapy.
• Subject is pregnant (according to Ulti Med hCG urine test) or breastfeeding.
• Subject is a woman of childbearing potential who does not agree to apply appropriate contraception methods during study participation and continues to do so for at least 6 months after study completion.
• Subject is a man with a pregnant or non-pregnant WOCBP partner, who does not agree to use a condom and continue to do so until 90 days after study completion. In addition, the non-pregnant WOCBP partner should use a highly effective method of contraception.

To be determined