Preclinical dose assessment of (S)-(-)- [¹⁸F]fluspidine and (R)-(+)-[¹⁸F]fluspidine, new PET tracers for imaging of σ₁ receptors.

Objectives : [¹⁸F]fluspidine (FPD) is a new σ₁ receptor radioligand for imaging of cancer and neuropsychiatric diseases which consists of two enantiomers of different kinetics and affinity. Biodistribution, organ doses (ODs) and effective dose (ED) of (S)-(-)-FPD# (Ki=2.3nM) and (R)-(+)-FPD## (Ki=0,52nM) were determined in mice to assess the radiation risk to humans.

Methods : 28#/22## female CD1 mice (29.8±2.2g#/29.3±1.9g##) were injected with 0.35±0.08MBq# and 0.39±0.05MBq## FPD into tail vein. At 5, 15, 30, 45, 60, 90, 120, 180 and 240 min. p.i. they were sacrificed and organ masses and activity determined. The fractions of activity were displayed as %ID. Time and mass were scaled to human magnitude. Using OLINDA/EXM, the cumulated activity in source organs and ODs were calculated.

Results : For (S)-(-)-FPD the adrenals received the highest OD [µSv/MBq] (36.0), followed by the kidneys (35.6). The highest contribution to ED (ICRP103, [µSv/MBq]) was by lungs (3.7) and upper large intestine (2.0). For (R)-(+)-FPD the lungs receive the highest OD (45.5), followed by the kidneys (27.6). The highest contribution to ED was by lungs (5.5) followed by ovaries (2.0). The estimated ED is 16.7#/18.4##. Considering 40% underestimation in preclinical dosimetry [1] for 300MBq of FPD i.v. the expected ED to humans is 8.4# and 9.2## [mSv].

Conclusions : Considerable differences in ODs were observed between the enantiomers. However, the putative ED to humans is within the range of what is caused by other ¹⁸F-labeled compounds. The results support the further development of the radioligands as a clinical tool for brain and cancer PET-imaging.

[1] Sattler B, …, Sabri O. Incorporation dosimetry of F-18-Flubatine - Comparison of animal model data with first-in-man results J. Nucl. Med. 2012; 53(suppl): 1503.

Research Support: The trial is funded by the german research organization (AO599719)