Preclinical dose assessment and biodistribution of [F-18]DBT-10, a new α7 nicotinic acetylcholine receptor (α7-nAChR) imaging ligand.

Objectives :

In vivo imaging of α7-nAChR provide important information for CNS disorders such as schizophrenia, Alzheimer disease, brain tumors etc. Due to the lack of suitable radiotracers a new structure, DBT-10 (Ki=0.3nM), was developed for brain imaging. To assess the radiation risk to humans after i.v. injection the biodistribution, organ doses (OD) and the effective dose (ED) were determined in mice (M) and piglets (P).

Methods :

Image based (M: Mediso nanoScan PET/MRI, P: SIEMENS Biograph16 PET/CT) whole body dosimetry was performed in 3 female M (age: 11 w, weight: 27.8 g) and 3 female P (age: 7 w, weight: 15.8 kg). The anesthetized animals were PET-imaged up to 5h post i.v. injection of 13.1 MBq, 165.5 MBq [¹⁸]DBT-10, followed by iterative reconstruction including MR- or CT-based attenuation correction respectively. The organs were defined by volumes of interest. Exponential curves were fitted to the time-activity-data (%ID/g). Time and mass were adapted to the human scale. The ODs were calculated using OLINDA and the ED using tissue weighting factors (ICRP103).

Results:

Following the i.v. injection of [¹⁸]DBT-10 no adverse effects on the basis of vital function monitoring were observed. The highest OD [µSv/MBq] was received in M by pancreas (35.5) and urinary bladder (30.0), in P by pancreas (60.8) and spleen (58.8). The highest contribution to ED [µSv/MBq] was in M by red marrow (2.4) and lungs (1.5), in P by liver (2.0) and lungs (1.9). The estimated ED [µSv/MBq] to humans is 12.7 (M), 13.7 (P).

Conclusions :

Considering an underestimation of 40% in preclinical dosimetry, the radiation risk, to humans (M: 6.4 mSv/300MBq, P: 6.8 mSv/300MBq) is well within the range of other F-18 labeled radiotracers. These results encourage to transfer [¹⁸]DBT-10 to the clinical study phase and further develop it as a clinical tool for imaging of α7-nAChR.

References:

[1] M.Schrimpf, K. Sippy, C. Briggs et al., SAR of α7 nicotinic receptor agonists derived from tilorone: Exploration of a novel nicotinic pharmacophore, Bioorganic & Medicinal Chemistry Letters, Volume 22, Issue 4, 15 February 2012, Pages 1633-1638, ISSN 0960-894X.

[2] B. Sattler, M. Kranz, M. Patt et al. Incorporation dosimetry of F-18-Flubatine - Comparison of animal model data with first-in-man results. Journal of Nuclear Medicine 2012; 53(suppl): 1503.