A first-in-man PET study of [18F]PSS232, a fluorinated ABP688 derivative for imaging metabotropic glutamate receptor subtype 5.

Purpose: Non-invasive imaging of metabotropic glutamate receptor 5 (mGlu₅) in the brain using PET is of interest in e.g., anxiety, depression, and Parkinson’s disease. Widespread application of the most widely used mGlu₅ tracer, [¹¹C]ABP688, is limited by the short physical half-life of carbon-11. [¹⁸F]PSS232 is a fluorinated analog with promising preclinical properties and high selectivity and specificity for mGlu₅. In this first-in-man study, we evaluated the brain uptake pattern and kinetics of [¹⁸F]PSS232 in healthy volunteers.Methods: [¹⁸F]PSS232 PET was performed with ten healthy male volunteers aged 20-40 years. Seven of the subjects received a bolus injection and the remainder a bolus/infusion protocol. Cerebral blood flow was determined in seven subjects using [¹⁵O]water PET. Arterial blood activity was measured using an online blood counter. Tracer kinetics were evaluated by compartment modeling and parametric maps were generated for both tracers.Results: At 90 min post-injection, 59.2 ± 11.1% of total radioactivity in plasma corresponded to intact tracer. The regional first pass extraction fraction of [¹⁸F]PSS232 ranged from 0.41 ± 0.06 to 0.55 ± 0.03 and brain distribution pattern matched that of [¹¹C]ABP688. Uptake kinetics followed a simple two-tissue compartment model. The volume of distribution of total tracer (<italic>V</italic>_T, ml/cm³) ranged from 1.18 ± 0.20 for white matter to 2.91 ± 0.51 for putamen. The respective mean distribution volume ratios (DVR) with cerebellum as the reference tissue were 0.88 ± 0.06 and 2.12 ± 0.10, respectively. The tissue/cerebellum ratios of a bolus/infusion protocol (30/70 dose ratio) were close to the DVR values.Conclusions: Brain uptake of [¹⁸F]PSS232 matched the distribution of mGlu₅ and followed a two-tissue compartment model. The well-defined kinetics and the possibility to use reference tissue models, obviating the need for arterial blood sampling, make [¹⁸F]PSS232 a promising fluorine-18 labeled radioligand for measuring mGlu₅ density in humans. [ABSTRACT FROM AUTHOR]