Preclinical dose assessment of [¹⁸F]fluspidine with PET/MRI: Enantiomeric differences in tracer kinetics cause a significant deviation in dosimetry

Objectives:

[¹⁸F]fluspidine is a PET radioligand for neuroimaging of σ1 receptors. The two enantiomers have different kinetics and affinities [1]. Biodistribution, organ doses (OD) and the effective dose (ED) of (S)-(—)-fluspidine (S) and (R)-(+)-fluspidine (R) were determined in mice using PET/MRI to assess the radiation risk to humans.
Methods:
Six female CD1 mice (weight: 30.9±1.3 g) were injected i.v. with 13.2±3.0 MBq (S, n=3) or 12.6±1.4 MBq (R, n=3), respectively. A dynamic 2 h animal PET/MR study was performed. All relevant organs were defined by volumes of interest. Time- and mass-scales were adapted to the human anatomy; exponential curves were fitted to the time-activity-data (%ID/organ). The ODs were computed using the adult male model with OLINDA and the ED using tissue weighting factors (ICRP103).
Results:
For S the highest OD [µSv/MBq] was received by urinary bladder (UB) (58.0), followed by kidneys (37.6). The highest contribution to ED [µSv/MBq] was by UB (2.32) and red marrow (1.30).For R the UB received the highest OD (55.7), followed by small intestine (22.6). The highest contribution to ED was by UB (2.23) and upper large intestine (1.54). The estimated EDs (S: 12.9±0.4; R: 14.0±0.5) differ significantly (p<0.05, student's t-test).
Conclusion:
The estimated ED is well within the range of other ¹⁸F-labeled radiotracer and supports further translational research. Furthermore, we have demonstrated that the enantiomer with higher affinity and slower kinetics (R) causes a higher dosimetric burden than its counterpart (S).
References:
[1] Brust, P. et al. "Distinctive In Vivo Kinetics of the New σ1 Receptor Ligands (R)-(+)-and (S)-(–)-¹⁸F-Fluspidine in Porcine Brain." Journal of Nuclear Medicine 55.10 (2014): 1730-1736.