Synthesis and evaluation of 15-(4-(2-[¹⁸F]Fluoroethoxy)phenyl)pentadecanoic acid: a potential PET tracer for studying myocardial fatty acid metabolism

Abstract

15-(4-(2-[¹⁸F]fluoroethoxy)phenyl)pentadecanoic acid ([¹⁸F]7) was synthesized as a PET probe for assessing myocardial fatty acid metabolism. The radiosynthesis of [¹⁸F]7 was accomplished using a two-step reaction, starting with the corresponding tosylate ester, methyl 15-(4-(2-(tosyloxy)ethoxy)phenyl)pentadecanoate (5), and gave the radiolabeled fatty acid, [¹⁸F]7 in a radiolabeling yield of 55-60% and a specific activity of >2000 Ci/mmol (decay corrected to EOB). The biological evaluation of [¹⁸F]7 in rats displayed high uptake in heart (1.94%ID/g at 5 min), which was higher than the uptake (%ID/g) in blood, lung, muscle, pancreas, and brain. MicroPET studies of [¹⁸F]7 in Sprague-Dawley rats demonstrated excellent images of the myocardium when compared with [¹¹C]palmitate images in the same animal. Moreover, the tracer kinetics of [¹⁸F]7 paralleled those seen with [¹¹C]palmitate, with an early peak followed by biphasic washout. When compared to [¹¹C]palmitate, [¹⁸F]7 exhibited a slower early clearance (0.17 ± 0.01 vs 0.30 ± 0.02, P < 0.0001) and a significantly higher late clearance (0.0030 ± 0.0005 vs 0.0006 ± 0.00013, P < 0.01). These initial studies suggest that [¹⁸F]7 could be a potentially useful clinical PET tracer to assess abnormal myocardial fatty acid metabolism.

Figure 1

Radiolabeled fatty acid analogs used in PET and SPECT imaging studies.

Figure 2

MicroPET imaging studies of [¹¹C]palmitate (Panel A) and [¹⁸F]7 (Panel B) in male Sprague-Dawley rats. Images are displayed on the transaxial axis and represent data acquired 20–30 min post-injection of the radiotracer. [¹⁸F]7 images display excellent quality and higher tracer accumulation than the [¹¹C]palmitate images. Tissue-time-activity curve are shown in Panel C for [¹¹C]palmitate and Panel D for [¹⁸F]7. Both radiotracers display biphasic washout kinetics but some differences are noted. For example, when compared to [¹¹C]palmitate, [¹⁸F]7 exhibited an early plateau followed by a slower early tracer clearance (0.17 ± 0.01 vs. 0.30 ± 0.02, P < 0.0001); and a significantly higher late clearance (0.0030 ± 0.0005 vs. 0.0006 ± 0.00013, P<0.01).

Scheme 1

Synthesis of the precursor for radiolabeling and the HPLC standard. Reagents and conditions: (a) trimethylsilyl diazomethane, THF, hexane, 2hr; (b) 4-benzyloxyphenylboronic acid, Pd(OAc)₂, [HP(t-Bu)₂Me]BF₄, KO-t-Bu, t-amyl alcohol, argon, RT; (c) 98% sulfuric acid, methanol; (d) Pd/c, EtOAc,H₂; (e) BrCH₂CH₂F, K₂CO₃, acetone; (f) TsOCH₂CH₂OTs, K₂CO₃, CH₃CN, reflux; g), 2N NaOH, aqueous MeOH.

Scheme 2

Radiosynthesis of [¹⁸F]7. Reagents and conditions (a) [`⁸F:F- Kryptof × 222 K₂CO₃ CH₃CN 80°C (b) 2N NaOH/MeOH H₂O (c) 1N HC