Radiosynthesis of [123I]N-methyl-4-iododexetimide and [123I]N-methyl-4-iodolevetimide: In vitro and in vivo characterisation of binding to muscarinic receptors in the rat heart

[123I]N-methyl-4-iododexetimide, [123I]MIDEX, and its pharmacologically inactive enantiomer [123I]N-methyl-4-iodolevetimide, [123I]MILEV were prepared via electrophilic iododesilylation using Chloramine-T as oxidising agent followed by N-methylation using methyl iodide. The radiotracers were purified with semi-preparative HPLC with radiochemical yields of 80 ± 11% (n = 6). The average time of synthesis was 100 min with specific activity >2000 Ci/mmol. In vitro, the binding of [123I]MIDEX, after addition of carrier, measured on homogenates of rat atrium was Bmax = 4.5 ± 0.4 pmol/mg protein, Kd = 3.3 ± 0.2 nM while in the ventricle Bmax = 2.3 ± 0.2 pmol/mg protein, Kd = 4.0 ± 1.4 nM. In vitro, the binding of [123I]MILEV was non-specific. The in vivo biodistribution of [123I]MIDEX showed high uptake in the atrium (3.2% ID/g) and left and right ventricles (2.2, 2.5% ID/g respectively) at 5 min followed by clearance. High heart-to-lung and moderate liver-to-lung ratios were obtained during 60 min. Radioactivity in the atrium and ventricles was reduced by pre-administration of the m-AChR antagonist MQNB (1 mg/kg). Pretreatment of rats with other m-AChR ligands, pirenzapine (M1), methoctramine (M2) and 4-DAMP (M3) also resulted in reduction of [123I]MIDEX uptake with methoctramine being the most potent. [123I]MIDEX distribution in the rat heart was not significantly inhibited by pre-administration of selective adrenergic drugs. The uptake was highly stereoselective since the inactive enantiomer, [123I]MILEV, demonstrated very low myocardial retention. The stability of [123I]MIDEX was evaluated by performing a metabolite study on atrium samples which revealed unchanged radiotracer 60 min postinjection. These results suggest that [123I]MIDEX may be a useful single photon agent for in vivo imaging of myocardial m-AChR in humans with [123I]MILEV offering the potential of assessing non-specific binding of the active tracer. © 1996 Published by Elsevier Inc.

Keywords

Receptors, Genes, Chloramines, Rats, Rodents, In vivo, Heart, Lungs, Liver, Drugs, Tracer techniques

Citation

Kassiou, M., Mardon, K., Katsifis, A. G., Najdovski, L., Dikic, B., Mattner, F., Lambrecht, R. M., Hicks, R. J., Eu, P., & Loc'h, C. (1996). Radiosynthesis of [123I]N-methyl-4-iododexetimide and [123I]N-methyl-4-iodolevetimide: In vitro and in vivo characterisation of binding to muscarinic receptors in the rat heart. Nuclear Medicine and Biology, 23(2), 147-153. doi:10.1016/0969-8051(95)02045-4