Preparation and First Preclinical Evaluation of [18F]FE@SNAP: A Potential PET Tracer for the Melanin Concentrating Hormone Receptor 1 (MCHR1)

Abstract

The melanin-concentrating hormone (MCH) system is a new target for the treatment of human disorders. Since the knowledge of the MCH system’s involvement in a variety of pathologies (obesity, diabetes, and deregulation of metabolic feedback mechanism) is based on in vitro or preclinical studies, a suitable positron emission tomography (PET) tracer needs to be developed. We herein present the preparation and first preclinical evaluation of [18F]FE@SNAP – a new PET tracer for MCH receptor-1 (MCHR1). The synthesis was performed using a microfluidic device. Preclinical evaluation included binding affinity, plasma stability, plasma free fraction, stability against the cytochrome P-450 (CYP450) system using liver microsomes, stability against carboxyl-esterase, and methods to assess the penetration of the blood-brain barrier (BBB) such as logD analysis and immobilized artificial membrane (IAM) chromatography. Levels at 374 ± 202 MBq [18F]FE@SNAP were obtained after purification. The obtained Kd value of [18F]FE@SNAP was 2.9 nM. [18F]FE@SNAP evinced high stability against carboxylesterase, CYP450 enzymes, and in human plasma. LogD (3.83) and IAM chromatography results (Pm=0.51) were in the same range as for known BBB-penetrating compounds. The synthesis of [18F]FE@SNAP was reliable and successful. Due to high binding affinity and stability, [18F]FE@SNAP is a promising tracer for MCHR1.

In vivo evaluation of radiotracers targeting the melanin-concentrating hormone receptor 1: [11C]SNAP-7941 and [18F]FE@SNAP reveal specific uptake in the ventricular system

“…6 ). The result may be biased due to the higher specific uptake in the ventricular system of [ 11 C]SNAP-7941 and the fast metabolism of [ 18 F]FE@SNAP 30 . Knowing from initial preclinical experiments with [ 11 C]SNAP-7941 31 , the low uptake in MCHR1 rich regions in the brain may be caused by limited blood-brain-barrier penetration due to binding to P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).…”

“…Radiosynthesis of [ 11 C]SNAP-7941, the radiolabeled analogue of (±)-SNAP-7941, was performed in a fully automated synthesizer (TRACERlab™ FX C Pro, GE Healthcare, Germany) as previously reported 28 . Radiosynthesis of [ 18 F]FE@SNAP was performed in a microfluidic device (Advion NanoTek®, Ithaca, NY, USA) as described elsewhere 29 , 30 , followed by a purification in a conventional synthesizer unit (Nuclear Interface®, GE Medical Systems, Uppsala, Sweden). Both radiotracers are formulated in physiological saline solution for intravenous injection.…”

“…1c ) was performed 28 , 29 . Since both tracers yield adequate amounts of radioactivity with suitable molar activity, initial preclinical evaluation has been accomplished 30 , 31 .

Figure 1 Chemical structures of the MCHR1 antagonists.

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The Potential Role of the MCHR1 in Diagnostic Imaging: Facts and Trends

“…The plasma-free fraction was lower (f1 = 12.6 ± 0.2%) than for [ 11 C]SNAP-7941, but can still be considered high enough for imaging. Compared with SNAP-7941, the lipophilicity was slightly higher: logD 7.4 = 3.83 [76].…”

“…As mentioned before, Borowsky et al [51] presented the evaluation of the very potent MCHR1 antagonist SNAP-7941, which contains a methyl ester (Figure 3(1)), making it suitable for radiolabeling introducing either a [ 11 C]methyl moiety or a 2-[ 18 F]fluoroethyl moiety. On this basis, two potential PET tracers for the visualization of the MCHR1 were developed so far: Figure 3(2)) and [ 18 F]FE@SNAP (Figure 3(3)) [73][74][75][76][77].…”