Synthesis, Fluorine-18 Radiolabeling, and Biological Evaluation of N-((E)-4-Fluorobut-2-en-1-yl)-2β-carbomethoxy-3β-(4′-halophenyl)nortropanes: Candidate Radioligands for In Vivo Imaging of the Brain Dopamine Transporter with Positron Emission Tomography

Abstract

The N-(E)-fluorobutenyl-3β-(para-halo-phenyl)nortropanes 9-12 were synthesized as ligands of the dopamine transporter (DAT) for use as 18F-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 [18F]9-[18F]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 [18F]9. PET imaging with [18F]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 post-injection of [18F]9 the ratio of uptake in the putamen and caudate vs. cerebellum uptake was ≥ 4.

Radiosynthesis and Validation of 18F-FP-CMT, a Phenyltropane with Superior Properties for Imaging the Dopamine Transporter in Living Brain

“…However, because of constraints imposed by radionuclides other than 18 F in combination with the kinetic profiles of the available radiotracers in the required imaging protocols, there remains a need for a tracer with optimal properties for quantitative imaging of multiple animals from a single radiosynthesis. Although, a plethora of agents have been developed for imaging of DAT, [1][2][3] all may suffer in varying degrees from lack of selectivity, unfavorable kinetics, and adverse metabolism. A particular issue is the pharmacological selectivity of tracers for DAT versus serotonin transporters (SERT), and to a lesser extent (because of their low abundance) noradrenaline transporters (NET).…”

Identification andin vivoevaluation of a fluorine-18 rolipram analogue, [18F]MNI-617, as a radioligand for PDE4 imaging in mammalian brain

“…These were synthesized using the route shown in Scheme , where phenol 8 was synthesized from 3‐benzyloxy‐4‐methoxybenzaldehyde, and phenol 9 was synthesized from 3‐cyclopentoxy‐4‐(benzyloxy)benzaldehyde (Scheme ). O ‐Alkylation of the sodium salt of phenols 8 or 9 with the corresponding alkyl tosylates gave derivatives 10a–f and 11a–g …”

Preparation of 1-tosyloxy-4-substituted-2-butenes using Ag(I) salts

“…1–4 Radiolabeling was performed by reacting 1 with K 18 F/K 2.2.2 to give [ 18 F] 2 , which was then reacted with the various nortropanes to give the 18 F PET tracers. 1, 3, 5 Subsequently, trans -4-chloro-1-tosyloxy-2-butene ( 3 ) was prepared and reacted with the tolyl-nortropane to provide the N -( E )-chloro-2-butenyl-nortropane that could then be used as a one-step 18 F-radiolabeling precursor. 6 The preparation of 1 , 2 , and 3 all require multiple synthetic steps.…”

“…Previously, compound 1 was obtained by ditosylation of trans -1,4-dihydroxy-2-butene 1–5, 11, 12 which was obtained by reduction of 1,4-dihydroxy-2-butyne, 1, 4, 13, 14 reduction of dimethylfumarate, 2, 5 hydrolysis of trans -1,4-diacetoxy-2-butene, 3, 11, 15, 16 or cross-metathesis of allyl alcohol. 12 The previous methods all required multiple steps whereas our new method allows 1 to be obtained in high yield after a single step and mild conditions from commercially available 5 .…”