Author: Soza-Ried, Cristian ; Rösch, Frank ; Kramer, Vasko ; Juri, Carlos ; Amaral, Horacio ; Pruzzo, Rossana ; Riss, Patrick J ; Haeger, Arlette ; Chana-Cuevas, Pedro

IntroductionDegeneration of dopaminergic, nigrostriatal neurons is the hallmark of Parkinson disease (PD), and PET quantification of dopamine transporters is a widely accepted method for differential diagnosis between idiopathic PD and essential tremor. [18F]PR04.MZ is a new PET tracer with excellent imaging properties allowing for precise quantification of striatal and extrastriatal dopamine transporter. Here we describe our initial experience with [18F]PR04.MZ PET/CT in a larger cohort of healthy controls and PD patients as a proof-of-concept study for this tracer.MethodsEighteen healthy subjects, 19 early PD patients (Hoehn-Yahr I–II), and 13 moderate-advanced PD patients (Hoehn-Yahr III–IV) underwent static PET/CT scans 60 to 90 minutes after injection of 5.16 ± 1.03 mCi (191 ± 38 MBq) [18F]PR04.MZ. Specific binding ratios (SBRs) were calculated for caudate nucleus, anterior putamen, posterior putamen, substantia nigra (SNpc), compared between different groups and correlated with clinical ratings.Results[18F]PR04.MZ showed very high and specific uptake in the putamen, caudate, and substantia nigra pars compacta and very low nonspecific binding in other brain regions, and SBR values for the control group were 22.3 ± 4.1, 19.1 ± 3.5, and 5.4 ± 1.2, respectively. A reduction of SBR values was observed in all regions and in both initial and moderate PD, ranging from 35% to 89% (P < 0.001). The observed pattern of reduction was posterior putamen > anterior putamen > substantia nigra pars compacta > caudate, with contralateral posterior putamen being the most affected region. Rostrocaudal depletion gradient was evident in all PD patients and progression correlated with motor manifestations.Conclusions[18F]PR04.MZ PET/CT is a highly sensitive imaging modality for the detection of dopaminergic deficit in nigrostriatal pathways in PD.

01 Jul 2020·European Journal of Nuclear Medicine and Molecular Imaging

Pharmacokinetic evaluation of [18F]PR04.MZ for PET/CT imaging and quantification of dopamine transporters in the human brain

Article

Author: Chana-Cuevas, Pedro ; Pruzzo, Rossana ; Flores, Jonathan ; Riss, Patrick J ; Kramer, Vasko ; Soza-Ried, Cristian ; Hurtado, Ana ; Juri, Carlos ; Rösch, Frank ; Amaral, Horacio

PURPOSEDopamine 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.METHODSThirty-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.RESULTS[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.CONCLUSIONS[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.

01 Nov 2009·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Efficient microwave-assisted direct radiosynthesis of [18F]PR04.MZ and [18F]LBT999: Selective dopamine transporter ligands for quantitative molecular imaging by means of PET

Q3 · MEDICINE

Article

Author: Riss, Patrick J. ; Roesch, Frank

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.

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Indication	Highest Phase	Country/Location	Organization	Date
Diagnostic agents	Phase 1	-	Universidad de Santiago de Chile	-
Diagnostic agents	Phase 1	-	Pontificia Universidad Católica de Chile	-

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