[123I]-2.beta.-carbomethoxy-3.beta.-(4-iodophenyl)tropane: high-affinity SPECT (single photon emission computed tomography) radiotracer of monoamine reuptake sites in brain

Journal of Medicinal Chemistry
1991.0

Abstract

The potent cocaine congener 2β-carbomethoxy-3β-(4-fluorophenyl)tropane (CFT or WIN 35,428) labeled with tritium or ¹¹CH₃ is superior to [³H]cocaine or [¹¹C]cocaine as a radioligand for cocaine receptors due to higher affinity and longer residence time on dopamine-reuptake sites. To develop analogues suitable for PET and SPECT imaging, we synthesized and characterized 2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT, 3a), its N-demethylated derivative (nor-CIT, 4), and the C2α isomer (α-CIT, 3b). We prepared [¹²³I]-β-CIT from the tributyltin precursor of 3a and evaluated its in vitro binding and in vivo SPECT imaging in baboons. In vitro binding assays showed β-CIT had high affinity for dopamine reuptake sites (IC₅₀ 1.6 nM vs [³H]CFT) and serotonin reuptake sites (IC₅₀ 3.78 nM vs [³H]paroxetine). SPECT imaging in baboons revealed highest brain uptake in the striatum (peak at 154 min post-injection, striatal-to-cerebellar ratio 9.8) and hypothalamic/midbrain regions (peak at 43 min). In vivo displacement studies showed indatraline (a dopamine/serotonin reuptake inhibitor) decreased both striatal and hypothalamic activity, while citalopram (a selective serotonin reuptake inhibitor) selectively reduced hypothalamic activity. These results demonstrate [¹²³I]-β-CIT is a useful SPECT probe for monoamine reuptake sites in primate brain, with striatal activity associated with dopamine reuptake sites and hypothalamic activity with serotonin reuptake sites. Slow brain washout and low thyroid uptake (indicating slow deiodination) support its utility. [¹²³I]-β-CIT and [¹¹C]-β-CIT may serve as clinical markers for dopaminergic and serotonergic innervation in disorders like Parkinson's disease and depression.

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