Abstract
In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol−1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15–60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kg−1, i.p.), whole brain radioactivity uptake was diminished by 25%–40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned.
Highlights
L-type calcium channels (LTCCs) are cell membrane proteins expressed in most electrically-excitable cells and involved in assorted cellular functions, including neurotransmitter and hormone secretion, Ca2+homeostasis and gene expression [1,2]
The HPLC injector of a commercial radiosynthesis unit was loaded with a solution of 1 mg of 1 and 0.9 equivalents of tetrabutylammonium hydroxide in
80 μL of anhydrous DMF, and [11C]CH3I was passed through the loop in a stream of helium gas
Summary
L-type calcium channels (LTCCs) are cell membrane proteins expressed in most electrically-excitable cells and involved in assorted cellular functions, including neurotransmitter and hormone secretion, Ca2+homeostasis and gene expression [1,2]. A subunit of the LTCC was among the first to be associated with neuropsychiatric diseases, including schizophrenia and bipolar disorder [3,4]. While Ca2+-channel antagonists have a long history in the treatment of hypertension and cardiac disease [5], the promise these pharmaceuticals hold for treatment of neurological and psychiatric disorders has yet to come to fruition [6,7,8,9,10,11,12,13,14]. It is believed that LTCC antagonists protect dopamine neurons in the substantia nigra from degeneration associated with Parkinson’s disease by dopamine D2 receptor desensitization [15]. Isradipine is currently in clinical trials for the treatment of Parkinson’s disease [17] and has demonstrated efficacy for bipolar depression in a proof-of-concept study [18]
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