A. Carpinelli

Preparation of [11C] radioligands with high specific radioactivity on a commercial PET tracer synthesizer

High specific radioactivity is required for receptor studies with PET. Hereby we wish to report our experience using Nuclear Interface PET Tracer Synthesizer for preparation of Carbon-11 radioligands and modules modifications, which allowed to achieve high specific radioactivity.

Asymmetric synthesis and preliminary evaluation of (R)- and (S)-[11C]bisoprolol, a putative β1-selective adrenoceptor radioligand

(+/-)-1-[4-(2-Isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2-propanol (bisoprolol) is a potent, clinically used beta(1)-adrenergic agent. (R)-(+) and (S)-(-) enantiomers of bisoprolol were labelled with carbon-11 (t(1/2)=20.4 min) as putative tracers for the non-invasive assessment of the beta(1)-adrenoceptor subtype in the human heart and brain with positron emission tomography (PET). The radiosynthesis consisted of reductive alkylation of des-iso-propyl precursor with [2-11C]acetone in the presence of sodium cyanoborohydride and acetic acid. The stereo-conservative synthesis of (R)-(+) and (S)-(-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-amino-2-propanol to be used as the precursors for the radiosynthesis of [11C]bisoprolol enantiomers was readily accomplished by the use of the corresponding chiral epoxide in three steps starting from the commercially available hydroxybenzyl alcohol. The final labelled product (either (+) or (-)-1-[4-(-isopropoxyethoxymethyl)-phenoxy]-3- [11C]isopropylamino-2-propanol) was obtained in 99% radiochemical purity in 30 min with 15+/-5% (EOS, non-decay corrected) radiochemical yield and 3.5+/-1 Ci/micromol specific radioactivity. Preliminary biological evaluation of the tracer in rats showed that about 30% of heart uptake of [11C](S)-bisoprolol is due to specific binding. The high non-specific uptake in lung might mask the heart uptake, thus precluding the use of [11C](S)-bisoprolol for heart and lung studies by PET. The remarkably high uptake of the tracer in rat brain areas rich of beta-adrenergic receptors such as pituitary (1.8+/-0.3% I.D. at 30 min) was blocked by pre-treatment with the beta-adrenergic antagonists propranolol (45%) and bisoprolol (51%, p<0.05). [11C](S)-bisoprolol deserves further evaluation in other animal models as a putative beta(1) selective radioligand for in vivo investigation of central adrenoceptors.

Synthesis and in vivo evaluation of [11C]CGP62349, a new GABAB receptor antagonist

Abstract This paper describes the radiosynthesis of [11C]CGP62349, a potential ligand to assess GABAB receptors in vivo. 11C was introduced by O-methylation of the corresponding des-methyl precursor, namely CGP67780. The final product was obtained with a reliable method in good yield. The radioligand was tested in monkey, revealing negligible blood-brain barrier penetration and brain uptake, thus prompting us to search for a new target structure with a better lipophilicity.

Synthesis and in vivo evaluation of 3‐[11C]methyl‐(3‐methoxy‐naphthalen)‐2‐yl‐(1‐benzyl‐piperidin)‐4‐yl‐acetate (SB‐235753), as a putative dopamine D4 receptors antagonist for PET

(3-Methoxy-naphthalen)2-yl-(1-benzyl-piperidin)4-yl-acetate (SB-235753) was labelled with 11C (t1/2=20·4 min) as a putative radioligand for the non-invasive assessment of Dopamine D4 receptors in vivo with positron emission tomography (PET). n n n nThe precursor for the radiosynthesis 3-hydroxynaphthyl-2-[N-benzyl)-piperidyl]-acetate hydrochloride was prepared by a four-step synthesis starting from ethyl-4-pyridyl acetate. The radiolabelling consisted of methylation with [11C]methyltriflate in dimethylformamide in the presence of potassium hydroxide. [11C]SB-235753, was synthesised in 30 min with a radiochemical yield of 10±5% (EOS, non-decay corrected) with 99% radiochemical purity and specific radioactivity of 10±3 Ci/μmol. n n n nBiodistribution studies in rats with [11C]SB-235753 showed the uniform distribution of the tracer within different areas of the murine brain. At 30 min after injection 99% of the radioligand in plasma and 100% in cerebellum was metabolised. These findings suggest that [11C]SB-235753 can not be a suitable tracer for dopamine D4 receptor studies with PET. Copyright

Synthesis and in vivo evaluation of [11C]ICI 118551 as a putative subtype selective β2-adrenergic radioligand

Erytro-(+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[ iso-propylamino]-2-butanol (ICI 118551) a potent clinically used beta2 adrenergic antagonist, was labelled with carbon-11 (t1/2 = 20.4 min) as a potential radioligand for the non-invasive assessment of beta2 adrenergic receptors in the lung with positron emission tomography (PET). The radiolabelled compound was prepared by reductive N-alkylation of its des-isopropyl precursor with [2-11C]acetone. (+/-)-[11C]ICI 118551 was obtained in greater than 98% radiochemical purity in 30 min with a radiochemical yield of 15 + 5% (non-decay corrected) and a specific radioactivity 2.5 +/- 0.5 Ci/micromol. The biological evaluation of racemic erythro (+/-)-[11C]ICI 118551 in rats and Macaca Nemestrina shows a high radioactivity uptake in lung and heart. However, in both animal models no detectable displacement of lung radioactivity concentration was observed after pre-treatment with propranolol or ICI 118551, which indicates that in this organ, radioligand uptake is mostly due to non-specific binding. The biological data suggest that erythro (+/-)-[11C]ICI 118551 is not adequate to be further developed as a tracer for beta2 adrenergic receptor imaging in vivo.

[11C]RN5: A new agent for the in vivo imaging of myocardial α1-adrenoceptors

Abstract The radiolabelling with the positron-emitter Carbon-11 and the biological evaluation in rats of 3-[2-[4-(2-[ 11 C]methoxyphenyl)piperazin-1-yl]ethyl]pyrimido[5,4- b ]indole-2,4-dione ([ 11 C]RN5), α 1 -adrenoceptor antagonist ( K i =0.21 nM), as a putative radioligand for the non-invasive assessment of α 1 -adrenoceptors with positron emission tomography (PET) is reported. The radiosynthesis procedure consisted of O -methylation of des -methyl precursor with [ 11 C]methyl iodide in the presence of potassium hydroxide in dimethylformamide (DMF) at 80 °C. [ 11 C]RN5 was obtained in >99% radiochemical purity in 25 min with a radiochemical yield in the 20–30% range, end of synthesis (EOS) (non-decay corrected) and a specific radioactivity of 92.5±18.5 GBq/μmol. Pre-clinical studies in rats showed a high uptake of [ 11 C]RN5 in heart, spleen, adrenal gland, lung and kidney but not in the brain. Inhibition studies with high doses of different adrenergic antagonists indicate that more than 70% of myocardial uptake of [ 11 C]RN5 is due to specific binding to α 1 -adrenoceptors. Our results indicate that [ 11 C]RN5 is suitable to be further developed as a potential radioligand for the in vivo PET imaging of myocardial α 1 -adrenoceptors in humans.

Radiosynthesis of [123I]βCIT, a selective ligand for the study of the dopaminergic and serotoninergic systems in human brain

The procedure previously reported for the radiosynthesis of [123I]betaCIT was modified in order to improve both radiochemical yield and purity of betaCIT (2beta-carbomethoxy-3beta(4-iodophenyl) tropane) to be injected for SPECT (Single Photon Emission Computed Tomography) analysis imaging. The overall procedure, involving a HPLC purification step, results in quite good and reproducible yields of a highly purified tracer.