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

Abstract

Purpose

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.

Methods

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 (Vt) and binding potentials (BPnd). 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 Vts 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 BPnd 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 BPnd values of 14.82, 11.95, and 2.63 in putamen, caudate, and SNpc, respectively. BPnd 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 Vts or BPnds, and good test-retest reliability for precise quantification of DAT in human subjects.

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Acknowledgments

We would like to thank Dr. Geoff Warnock (PMod Technologies), Irene Coudeu, and Ana Hurtado (Positronmed) for their help during PET studies; Dr. Evelyng Faure (FALP, Chile) for acquiring MRI scans and Carlos Elgueta; and Dr. Mario Avila (Positronpharma) for assistance in tracer production.

Funding

This study was in part funded by the InnovaChile (CORFO), project 13PIE-21682. Carlos Juri was funded by Conicyt-Chile, project FONDECYT 11130534.

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Correspondence to Vasko Kramer.

Ethics declarations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the regional ethics committee board (CEC SSM Oriente, permit 20140520) and written informed consent has been obtained from all participants.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Key points

Question: To study and describe the pharmacokinetics and an adequate imaging and quantification protocol for [18F]PR04.MZ.

Pertinent findings: We evaluated metabolism, regional brain uptake, kinetic modeling, impact of scan duration, and test-retest variability and showed that [18F]PR04.MZ is a highly selective PET tracer for DAT, providing excellent imaging contrast and stable, reliable quantification outcomes within a reasonable time frame.

Implications for patient care: The high specific uptake, in particular, in SNpc is an advantage over existing methods and may have a clinical impact for patients being evaluated for movement disorders.

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Kramer, V., Juri, C., Riss, P.J. et al. Pharmacokinetic evaluation of [18F]PR04.MZ for PET/CT imaging and quantification of dopamine transporters in the human brain. Eur J Nucl Med Mol Imaging 47, 1927–1937 (2020). https://doi.org/10.1007/s00259-019-04594-z

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Keywords

  • [18F]PR04.MZ
  • Pharmacokinetics
  • Dopamine transporter
  • Parkinson’s disease
  • PET/CT