Synthesis and Imaging Validation of [¹⁸F]MDL100907 Enabled by Ni-Mediated Fluorination

Several voids exist in reliable positron emission tomography (PET) radioligands for quantification of the serotonin (5HT) receptor system. Even in cases where 5HT radiotracers exist, challenges remain that have limited the utility of 5HT imaging in clinical research. Herein we address an unmet need in 5HT_2a imaging using innovative chemistry. We report a scalable and robust synthesis of [¹⁸F]­MDL100907, which was enabled by a Ni-mediated oxidative fluorination using [¹⁸F]­fluoride. This first demonstration of a Ni-mediated fluorination used for PET imaging required development of a new reaction strategy that ultimately provided high specific activity [¹⁸F]­MDL100907. Using the new synthetic strategy and optimized procedure, [¹⁸F]­MDL100907 was evaluated against [¹¹C]­MDL100907 for reliability to quantify 5HT_2a in the nonhuman primate brain and was found to be superior based on a single scan analysis using the same nonhuman primate. The use of this new 5HT_2a radiotracer will afford clinical neuroscience research the ability to distinguish 5HT_2a receptor abnormalities binding between healthy subjects and patients even when group differences are small

PET Imaging of Fatty Acid Amide Hydrolase with [¹⁸F]DOPP in Nonhuman Primates

Fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [¹¹C]­CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [¹⁸F]­DOPP ([¹⁸F]­3-(4,5-dihydrooxazol-2-yl)­phenyl (5-fluoropentyl)­carbamate) has been identified as a promising ¹⁸F-labeled analogue based on rodent studies. The goal of this work is to evaluate [¹⁸F]­DOPP in nonhuman primates to support its clinical translation. High specific activity [¹⁸F]­DOPP (5–6 Ci·μmol^–1) was administered intravenously (iv) to three baboons (2M/1F, 3–4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [¹⁸F]­DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ∼95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [¹⁸F]­DOPP covalently links to the active site of FAAH. Consistent with previous findings for [¹¹C]­CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter <i>λk</i>₃ was therefore used to evaluate whole brain (WB) and regional binding of [¹⁸F]­DOPP. Pretreatment studies showed inhibition of <i>λk</i>₃ across all brain regions (WB baseline: 0.112 mL/cm³/min; 300 μg/kg URB597: 0.058 mL/cm³/min), suggesting that [¹⁸F]­DOPP binding is specific for FAAH, consistent with previous rodent data

Development of a Fluorinated Class‑I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance

Despite major efforts, our knowledge about many brain diseases remains remarkably limited. Epigenetic dysregulation has been one of the few leads toward identifying the causes and potential treatments of psychiatric disease over the past decade. A new positron emission tomography radiotracer, [¹¹C]­Martinostat, has enabled the study of histone deacetylase in living human subjects. A unique property of [¹¹C]­Martinostat is its profound brain penetrance, a feature that is challenging to engineer intentionally. In order to understand determining factors for the high brain-uptake of Martinostat, a series of compounds was evaluated in rodents and nonhuman primates. The study revealed the major structural contributors to brain uptake, as well as a more clinically relevant fluorinated HDAC radiotracer with comparable behavior to Martinostat, yet longer half-life

In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs

Epigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute to disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting in the context of cardiovascular disease and central nervous system dysfunction. Development of a molecular agent for non-invasive imaging to elucidate the distribution and functional roles of HDACs in humans will accelerate medical research and drug discovery in this domain. Herein, we describe the synthesis and validation of an HDAC imaging agent, [¹¹C]<b>6</b>. Our imaging results demonstrate that this probe has high specificity, good selectivity, and appropriate kinetics and distribution for imaging HDACs in the brain, heart, kidney, pancreas, and spleen. Our findings support the translational potential for [¹¹C]<b>6</b> for human epigenetic imaging

Positron Emission Tomography Assessment of the Intranasal Delivery Route for Orexin A

Intranasal drug delivery is a noninvasive drug delivery route that can enhance systemic delivery of therapeutics with poor oral bioavailability by exploiting the rich microvasculature within the nasal cavity. The intranasal delivery route has also been targeted as a method for improved brain uptake of neurotherapeutics, with a goal of harnessing putative, direct nose-to-brain pathways. Studies in rodents, nonhuman primates, and humans have pointed to the efficacy of intranasally delivered neurotherapeutics, while radiolabeling studies have analyzed brain uptake following intranasal administration. In the present study, we employed carbon-11 radioactive methylation to assess the pharmacokinetic mechanism of intranasal delivery of Orexin A, a native neuropeptide and prospective antinarcoleptic drug that binds the orexin receptor 1. Using physicochemical and pharmacological analysis, we identified the methylation sites and confirmed the structure and function of methylated Orexin A (CH₃-Orexin A) prior to monitoring its brain uptake following intranasal administration in rodent and nonhuman primate. Through positron emission tomography (PET) imaging of [¹¹C]­CH₃-Orexin A, we determined that the brain exposure to Orexin A is poor after intranasal administration. Additional ex vivo analysis of brain uptake using [¹²⁵I]­Orexin A indicated intranasal administration of Orexin A affords similar brain uptake when compared to intravenous administration across most brain regions, with possible increased brain uptake localized to the olfactory bulbs