[18F]-PR-04.MZ

Dopamine transporters (DAT) modulate pre-synaptic dopamine and physiological functions such as movement and reward. DAT also mirrors disease state in neurological disorders, rendering it an essential diagnostic target. [¹⁸F]PR04.MZ is a new PET imaging agent for DAT with an improved affinity and selectivity profile, for which we here describe the complete pharmacokinetic evaluation in healthy controls.

Thirty-two healthy subjects underwent T1-weighted MRI and dynamic PET scans for 180 min with arterial blood sampling (n = 5) or 90 min without blood sampling (n = 25) after injection of 197.6 ± 12.2 MBq [¹⁸F]PR04.MZ. Blood and plasma metabolite analysis were performed. MRI-based normalization of brain images, delineation of VOIs, and kinetic modeling was conducted to determine distribution volumes (V_t) and binding potentials (BP_nd). The impact of scan duration was evaluated and repeated PET scans were performed to assess test-retest variability (n = 5). A static imaging protocol has been validated for clinical applications.

[¹⁸F]PR04.MZ showed rapid metabolization in circulation, very high uptake in striatum and midbrain, and very low non-specific binding. The two-tissue compartment model 2TCM provided best fits for measured time-activity-curves and calculated V_ts in putamen, caudate, substantia nigra pars compacta (SNpc), and cerebellar cortex were 11.83, 9.73, 2.12, and 0.57, respectively. All non-invasive models correlated well with BP_nd values derived from 2TCM but underestimated DAT availability by about 28-33%. Of those, simplified reference tissue model (SRTM) provided the best fits, lowest Akaike Information Criteria values, and BP_nd values of 14.82, 11.95, and 2.63 in putamen, caudate, and SNpc, respectively. BP_nd estimates for striatal regions and SNpc were stable between 90 and 130 min post-injection. Test-retest results were excellent, showing low variability in all and excellent reliability in most relevant regions. Static imaging from 60 to 90-min post-injection is a viable alternative for quantification.

[¹⁸F]PR04.MZ is a PET tracer with very high affinity, selectivity, and specific uptake in striatum and midbrain. 2TCM and SRTM provide good fits, high and stable V_ts or BP_nds, and good test-retest reliability for precise quantification of DAT in human subjects.

PR04.MZ 8-(4-fluoro-but-2-ynyl)-3-p-tolyl-8-aza-bicyclo[3.2.1]octane-2-carboxylic acid methyl ester (1) and LBT999 8-((E)-4-fluoro-but-2-enyl)-3b-p-tolyl-8-aza-bicyclo[3.2.1]octane-2beta-carboxylic acid methyl ester (2) are selective dopamine reuptake inhibitors, derived from cocaine. Compounds 1 and 2 were labelled with fluorine-18 at their terminally fluorinated N-substituents employing microwave enhanced direct nucleophilic fluorination. K[(18)F]F(-) Kryptofix 222 cryptate, tetrabutyl ammonium [(18)F]fluoride and caesium [(18)F]fluoride were compared as fluoride sources under conventional and microwave enhanced conditions. Fluorination yields were remarkably increased under microwave irradiation for all three fluoride salts. Radiochemically pure (>98%) [(18)F]PR04.MZ (0.95-1.09GBq, 42-135GBq/micromol) was obtained within 34-40min starting from 3.0GBq [(18)F]fluoride ion in 32-36% non-decay-corrected overall yield using K[(18)F]F(-)Kryptofix 222 cryptate in MeCN.