Synthesis, fluorine-18 radiolabeling, and biological evaluation of N-((E)-4-fluorobut-2-en-1-yl)-2beta-carbomethoxy-3beta-(4'-halophenyl)nortropanes: candidate radioligands for in vivo imaging of the brain dopamine transporter with positron emission tomography

Abstract

The N-(E)-fluorobutenyl-3beta-(para-halo-phenyl)nortropanes 9-12 were synthesized as ligands of the dopamine transporter (DAT) for use as (18)F-labeled positron emission tomography (PET) imaging agents. In vitro competition binding assays demonstrated that compounds 9-12 have a high affinity for the DAT and are selective for the DAT compared to the serotonin and norepinephrine transporters. MicroPET imaging with [(18)F]9-[(18)F]11 in anesthetized cynomolgus monkeys showed high uptake in the putamen with lesser uptake in the caudate, but significant washout of the radiotracer was only observed for [(18)F]9. PET imaging with [(18)F]9 in an awake rhesus monkey showed high and nearly equal uptake in both the putamen and caudate with peak uptake achieved after 20 min followed by a leveling-off for about 10 min and then a steady washout and attainment of a quasi-equilibrium. During the time period 40-80 min postinjection of [(18)F]9, the ratio of uptake in the putamen and caudate vs cerebellum uptake was > or = 4.

Figure 1

MicroPET images (summed 0-145 min) obtained by injection of [¹⁸F]9 into an anesthetized cynomolgus monkey.

Figure 2

MicroPET baseline TACs obtained by injection of [¹⁸F]9 into an anesthetized cynomolgus monkey.

Figure 3

MicroPET TACs showing the result of injection of 19 (0.3 mg/kg) into an anesthetized cynomolgus monkey at 90 min post-injection of [¹⁸F]9.

Figure 4

MicroPET baseline TACs obtained by injection of [¹⁸F]10 into an anesthetized cynomolgus monkey.

Figure 5

MicroPET baseline TACs obtained by injection of [¹⁸F]11 into an anesthetized cynomolgus monkey.

Figure 6

MicroPET baseline TACs obtained by injection of [¹⁸F]13 into an anesthetized cynomolgus monkey.

Figure 7

HRRT PET images (summed 55-75 min) obtained by injection of [¹⁸F]9 into an awake rhesus monkey.

Figure 8

HRRT baseline TACs obtained by injection of [¹⁸F]9 into an awake rhesus monkey.

Figure 9

Graph of the ratio of uptake of [¹⁸F]9 in the caudate and putamen vs. cerebellum uptake with time for the HRRT awake rhesus monkey study shown in Figure 8.

Scheme 1