Efficient radiosynthesis and preclinical evaluation of [¹⁸F]FOMPyD as a positron emission tomography tracer candidate for TrkB/C receptor imaging

Abstract

Herein we report an efficient radiolabeling of a 18F‐fluorinated derivative of dual inhibitor GW2580, with its subsequent evaluation as a positron emission tomography (PET) tracer candidate for imaging of two neuroreceptor targets implicated in the pathophysiology of neurodegeneration: tropomyosin receptor kinases (TrkB/C) and colony stimulating factor receptor (CSF‐1R). [18F]FOMPyD was synthesized from a boronic acid pinacolate precursor via copper‐mediated 18F‐fluorination concerted with thermal deprotection of the four Boc groups on a diaminopyrimidine moiety in an 8.7±2.8% radiochemical yield, a radiochemical purity >99%, and an effective molar activity of 187±93 GBq/μmol. [18F]FOMPyD showed moderate brain permeability in wild‐type rats (SUVmax = 0.75) and a slow washout rate. The brain uptake was partially reduced (ΔAUC40–90 = 11.6%) by administration of the nonradioactive FOMPyD (up to 30 μg/kg). In autoradiography, [18F]FOMPyD exhibits ubiquitous distribution in rat and human brain tissues with relatively high nonspecific binding revealed by self‐blocking experiment. The binding was blocked by TrkB/C inhibitors, but not with a CSF‐1R inhibitor, suggesting selective binding to the former receptor. Although an unfavorable pharmacokinetic profile will likely preclude application of [18F]FOMPyD as a PET tracer for brain imaging, the concomitant one‐pot copper‐mediated 18F‐fluorination/Boc‐deprotection is a practical technique for the automated radiosynthesis of acid‐sensitive PET tracers.

Synthesis and Evaluation of a 18F-Labeled Ligand for PET Imaging of Colony-Stimulating Factor 1 Receptor

“…administration 5 min prior to radioligand injection, which might not have allowed time for sufficient blocking. However, most of the PET radioligands currently developed for CSF1R imaging have low uptake or high non-specific binding in the brains of rodents and non-human primates [ 25 , 27 , 28 ]. Moreover, a recent in vitro study of [ 3 H]CPPC showed off-target binding of CPPC to quite a number of kinases in the CNS; thus, [ 11 C]CPPC may have low selectivity for CSF1R [ 38 ].…”

“…Radioligands based on CSF1R inhibitors have been developed for PET studies of neuroinflammation ( Figure 1 ), such as 5-(4-((4-[ 18 F]fluorobenzyl)oxy)-3-methoxybenzyl)pyrimidine-2,4-diamine ([ 18 F]FOMPyD) [ 24 , 25 ], 5-(3-[ 11 C]methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine ([ 11 C]GW2580) [ 26 ], 4-(2,4-difluoroanilino)-7-ethoxy-6-(4-[ 11 C]methylpiperazin-1-yl)quinoline-3-carboxamide ([ 11 C]AZ683) [ 27 ], 4-((2-(((1 S ,2 R )-2-hydroxycyclohexyl)amino)benzo[ d ]thiazol-6-yl)oxy)- N -[ 11 C]methylpicolinamide ([ 11 C]BLZ945) [ 28 ], and 5-cyano- N -(4-(4-[ 11 C]methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([ 11 C]CPPC)) [ 18 , 29 ]. FOMPyD, a derivative of GW2580 (IC 50 = 10 nM for CSF1R), was reported as a dual type-II tropomyosin receptor kinase (TrK)/CSF1R inhibitor (IC 50 = 169 nM for CSF1R) [ 24 , 25 ]. Its 18 F-labeled form, [ 18 F]FOMPyD showed high non-specific binding in autoradiography of rat and human brain tissues, and the binding was not blocked with a known CSF1R inhibitor (BLZ945) [ 25 ].…”

“…FOMPyD, a derivative of GW2580 (IC 50 = 10 nM for CSF1R), was reported as a dual type-II tropomyosin receptor kinase (TrK)/CSF1R inhibitor (IC 50 = 169 nM for CSF1R) [ 24 , 25 ]. Its 18 F-labeled form, [ 18 F]FOMPyD showed high non-specific binding in autoradiography of rat and human brain tissues, and the binding was not blocked with a known CSF1R inhibitor (BLZ945) [ 25 ]. Recently developed [ 11 C]GW2580 demonstrated higher sensitivity than [ 11 C]CPPC in PET imaging of acute and chronic inflammation mouse models [ 26 ].…”

Simultaneous PET/MRI: The future gold standard for characterizing motor neuron disease—A clinico-radiological and neuroscientific perspective

“…While neurotrophins have not yet proven a significant therapeutic potential in clinical trials, partly because of the difficulties of protein delivery and pharmacokinetics in the nervous system, the binding target of neurotrophins includes a family of tyrosine kinase (TrK) receptors. Within this class of receptors, synthetic antibodies have recently been linked to PET-radioligands targeting the TrK-B receptor, which have passed the preclinical and clinical assessments ( 52 – 54 ). Quantitative characterization of TrK-B alterations in ALS is currently underway by the same research group, accounting for the volumetric changes inherent in the disease by applying PET/MRI in the first place, complemented by magnetic resonance spectroscopy data.…”

“…Quantitative characterization of TrK-B alterations in ALS is currently underway by the same research group, accounting for the volumetric changes inherent in the disease by applying PET/MRI in the first place, complemented by magnetic resonance spectroscopy data. The recent development of TrkB agonistic antibodies and BDNF-targeted gene therapies ( 55 , 56 ) could prove useful, and changes in TrK-B alterations as measured by PET/MRI during targeted therapy could potentially qualify as an imaging endpoint in clinical trials in motor neuron disease ( 52 – 54 , 57 ).…”