Proceedings: PET Drugs—A 2023 Workshop on Product Quality, Regulatory Submissions, Facility Inspections, and Benefit–Risk Considerations

Journal of Nuclear Medicine · 2025-07-24 · 2 citations

Advances in PET radiopharmaceutical technologies necessitate continued dialogue between members of the PET drug manufacturing community and the U.S. Food and Drug Administration (FDA) to ensure that these drugs continue to be safe and effective and are sustainably supplied in accordance with regulatory commitments and current good manufacturing practice (cGMP) regulations. After the success of the 2020 PET drugs workshop, the FDA hosted a follow-up public workshop entitled “PET: Product Quality, Regulatory Submissions, Facility Inspections, and Benefit–Risk Considerations.” The 2023 workshop addressed knowledge gaps that emerged during the 2020 workshop and themes from responses to a survey of PET drug manufacturers. The goal of this workshop was to support continued communication between the FDA and PET stakeholders to drive clarity toward PET cGMP regulations described in the <i>Code of Federal Regulations</i> (title 21, part 212) and PET Drug cGMP guidance documents, with the objective to improve compliance with PET drug manufacturing guidelines. In addition, investigational PET drugs (<i>Code of Federal Regulations</i>, title 21, part 312) were discussed, as they are intimately connected with the approval process and eventual cGMP manufacturing regulations once they matriculate to clinical use. The workshop was held on November 13–14, 2023, on the FDA campus in Silver Spring, MD. The Society of Nuclear Medicine and Molecular Imaging, the Medical Imaging and Technology Alliance, and the Coalition of PET Drug Manufacturers cosponsored the workshop with the FDA. This article summarizes the discussions that were conveyed at this workshop.

Noninvasive Detection of Oxidative Stress in a Mouse Model of 4R Tauopathy via Positron Emission Tomography with [18F]ROStrace

International Journal of Molecular Sciences · 2025-02-21 · 3 citations

Oxidative stress, defined as the excessive production of reactive oxygen species (ROS), is a crucial factor in the pathogenesis of various neurodegenerative diseases, including the 4-repeat (4R) tauopathies. Collectively, the 4R tauopathies are characterized by the progressive aggregation of tau protein isoforms with four microtubule-binding domains in and around brain cells. The cyclical relationship between oxidative stress and 4R tau aggregation suggests that a means of imaging ROS noninvasively could be a valuable tool for the study and treatment of 4R tauopathy in both humans and animal models. To demonstrate the potential of the ROS-sensitive positron emission tomography (PET) radiotracer [18F]ROStrace as a means of filling this methodological gap, we performed [18F]ROStrace PET imaging on PS19 mice, which exhibit 4R tau aggregation similar to that seen in human 4R tauopathy. Significant increases in [18F]ROStrace signal became detectable in the hippocampus of 6–11-month-old (mo) PS19 animals and spread to the brainstem, midbrain, and thalamus of 11+ mo animals. Additionally, older PS19 mice displayed higher whole-brain average [18F]ROStrace signal compared to age-matched controls (p = 0.042), and tau pathology consistently colocalized with multiple fluorescent indicators of oxidative stress in PS19 brain samples. These results provide novel evidence that 4R tau aggregation is associated with increased oxidative stress in PS19 mouse brain and advance [18F]ROStrace as a noninvasive technology for the detection of oxidative stress in neurodegenerative diseases involving tau pathology.

Toward a Small-Molecule Antagonist Radioligand for Positron Emission Tomography Imaging of the Mu Opioid Receptor

ACS Chemical Neuroscience · 2025-03-29 · 1 citations

The opioid crisis is a catastrophic health emergency catalyzed by the misuse of opioids that target and activate the mu opioid receptor. Many traditional radioligands used to study the mu opioid receptor are often tightly regulated owing to their abuse and respiratory depression potential. Of those that are not regulated, a lack of opioid receptor subtype selectivity can cause confounding in interpreting results. In the present study, we sought to design and characterize a library of 24 antagonist ligands for the mu opioid receptor. Ligands were evaluated for the binding affinity, intrinsic activity, and predicted blood–brain barrier permeability. Several ligands demonstrated single-digit nM binding affinity for the mu opioid receptor while also demonstrating selectivity over the delta and kappa opioid receptors. The antagonist behavior of 1A and 3A at the mu opioid receptor indicate that these ligands would likely not induce opioid-dependent respiratory depression. Therefore, these ligands can enable a safer means to interrogate the endogenous opioid system. Based on binding affinity, selectivity, and potential off-target binding, [11C]1A was prepared via metallophotoredox of the aryl-bromide functional group to [11C]methyl iodide. The nascent radioligand demonstrated brain uptake in a rhesus macaque model and accumulation in the caudate and putamen. Naloxone was able to reduce [11C]1A binding, though the interactions were not as pronounced as naloxone’s ability to displace [11C]carfentanil. These results suggest that GSK1521498 and related congeners are amenable to radioligand design and can offer a safer way to query opioid neurobiology.

Pilot Study of [11C]HY-2-15: A Mixed Alpha-Synuclein and Tau PET Radiotracer

Cells · 2025-07-26 · 2 citations

A novel brain positron emission tomography (PET) radioligand, [11C]HY-2-15, has potential for imaging alpha-synuclein aggregations in multiple system atrophy and misfolded tau proteins in tauopathies, based on its high binding affinity in disease brain tissue homogenates. Here, we demonstrate that [3H]HY-2-15 has the capability to bind to aggregated alpha-synuclein in multiple system atrophy brain and tau aggregations in progressive supranuclear palsy and corticobasal degeneration brain tissues via in vitro autoradiography study. A first-in-human pilot multicenter clinical study recruited a total of 10 subjects including healthy controls and patients with Parkinson’s disease, multiple system atrophy, or progressive supranuclear palsy. The study revealed that [11C]HY-2-15 has a relatively higher specific uptake in the pallidum and midbrain of patients with progressive supranuclear palsy. Total-body scans performed on the PennPET Explorer showed the radiotracer was cleared by renal excretion. However, the rapid metabolism and low brain uptake resulted in a limited signal of [11C]HY-2-15 in brain.

Photomediated Radiohalogenation of Aryl Thianthrenium Salts Using 77Br, 125I, and 211At

Nuclear Medicine and Biology · 2025-11-01

Mu-opioid receptor availability in patients with opioid use disorder treated with either methadone or buprenorphine

medRxiv · 2025-10-08

Abstract Methadone (MET) and buprenorphine (BUP)—mu-opioid receptor (MOR) agonists—are efficacious treatments for opioid use disorder (OUD). Using high-sensitivity, long axial field-of-view PET imaging with [ 11 C]carfentanil, we compared MOR availability in 5 MET and 5 BUP patients and 13 healthy controls (HCs) in five brain regions: ventral tegmentum, thalamus, caudate, putamen, and amygdala. MOR availability differed across groups (F 10,34 =5.6, p&lt;0.001) and was lower in BUP patients than HCs across all brain regions (mean reduction=39.1±15.2%; p&lt;0.001), lower in MET patients than HCs in the ventral tegmentum and amygdala (p’s&lt;0.05), and lower in BUP than MET patients in four of five regions (p’s&lt;0.05). MOR availability was inversely related to serum drug levels, linear for MET (R²=0.83, linear) and logarithmic for BUP (R²=0.96). [ 11 C]carfentanil PET may be useful in guiding personalized OUD treatment based on receptor engagement, which differs significantly between the two opioid agonist treatments. Studies are needed to link MOR availability with specific clinical characteristics (e.g., hedonic capacity, MOR agonist-associated weight gain) and OUD treatment outcomes.

PARP1-targeted alpha therapy enhances target expression

EJNMMI Research · 2025-06-01

Abstract Graphical abstract

[ ¹¹ C]Carfentanil PET Whole-Body Imaging of μ-Opioid Receptors: A First in-Human Study

Journal of Nuclear Medicine · 2025-05-08

μ-opioid receptors (MORs) are G-coupled receptors widely expressed in the brain and body. MORs have a high affinity for both endogenous opioids such as β-endorphins and exogenous opioids such as fentanyl. They mediate pain and reward and have been implicated in the pathophysiology of opioid, cocaine, and other substance use disorders. Using an instrument with a long axial field of view and the MOR-selective radioligand [¹¹C]carfentanil, we measured the whole-body distribution of MORs in 13 healthy humans. We also examined sex differences in MOR distribution at baseline and after pretreatment with the MOR antagonist naloxone. <b>Methods:</b> Six female and 7 male healthy subjects underwent 2 [¹¹C]carfentanil PET imaging sessions—one at baseline and one immediately after pretreatment with the MOR antagonist naloxone (13 μg/kg). Whole-body PET imaging was performed on an instrument with a 142-cm axial bore. [¹¹C]carfentanil brain distribution volume ratios were determined using the occipital cortex and the visual cortex within it as reference regions. For peripheral organ distribution volume ratios, the descending aorta and proximal-extremity muscle (biceps/triceps) were used as reference regions. <b>Results:</b> Naloxone blockade reduced MOR availability by 40%–50% in the caudate, putamen, thalamus, amygdala, and ventral tegmentum, brain regions known to express high levels of MORs. Women showed greater receptor occupancy in the thalamus, amygdala, hippocampus, and frontal and temporal lobes and a greater naloxone-induced reduction in thalamic MOR availability than men (<i>P</i> &lt; 0.05). For determining brain MOR availability, there was less variance in the visual cortex than in the occipital cortex reference region. For peripheral MOR determination, the descending aorta reference region showed less variance than the extremity muscle, but both showed blocking effects of naloxone. <b>Conclusion:</b> [¹¹C]carfentanil whole-body PET scans are useful for understanding MOR physiology under both baseline and blocking conditions. Extra–central nervous system reference regions may be useful for quantifying radiotracers when a region devoid of binding in the central nervous system is unavailable. The long axial field of view was useful for measuring changes in the short-lived radiotracer [¹¹C]carfentanil, with and without naloxone blocking. Further research is needed to evaluate the behavioral and clinical relevance of sex differences in naloxone–MOR interactions.

Author response for "The development of a PET Radiotracer for Imaging Alpha Synuclein Aggregates in Parkinson’s Disease"

2025-02-26

[ ¹¹ C]Carfentanil PET Whole-Body Imaging of Mu-Opioid Receptors: A First In-Human Study

medRxiv · 2025-01-01 · 1 citations

Abstract Introduction Mu-opioid receptors (MORs) are G-coupled protein receptors with a high affinity for both endogenous and exogenous opioids. MORs are widely expressed in the central nervous system (CNS), peripheral organs, and the immune system. They mediate pain and reward and have been implicated in the pathophysiology of opioid, cocaine, and other substance use disorders. Using the long axial field-of-view (LAFOV) PennPET Explorer instrument and the MOR selective radioligand [ 11 C]carfentanil ([ 11 C]CFN), we measured the whole-body distribution of MORs in 13 healthy humans. We also examined sex differences in MOR distribution at baseline and after pretreatment with the MOR antagonist naloxone. Methods Six female and seven male healthy subjects underwent two [ 11 C]CFN PET imaging sessions—one at baseline and one immediately following pre-treatment with the MOR antagonist naloxone (13 mcg/kg). Whole-body PET imaging was performed on the PennPET Explorer, a 142-cm axial bore instrument. [ 11 C]CFN brain distribution volume ratios (DVRs) were determined using the occipital cortex and the visual cortex within it as reference regions. For peripheral organ DVRs, the descending aorta and proximal extremity muscle (biceps/triceps) were used as reference regions. Results Naloxone blockade reduced MOR availability by 40-50% in the caudate, putamen, thalamus, amygdala, and ventral tegmentum, brain regions known to express high levels of MORs. Women showed greater receptor occupancy in the thalamus, amygdala, hippocampus and frontal and temporal lobes and a greater naloxone-induced reduction in thalamic MOR availability than men (p’s &lt;0.05). For determining brain MOR availability, there was less variance in the visual cortex than the occipital cortex reference region. For peripheral MOR determination, the descending aorta reference region showed less variance than the extremity muscle, but both showed blocking effects of naloxone. Conclusions [ 11 C]CFN whole- body PET scans are useful for understanding MOR physiology under both baseline and blocking conditions. Extra-CNS reference regions may be useful for quantifying radiotracers when a region devoid of binding in the CNS is unavailable. The LAFOV PET instrument was useful for measuring changes in the short-lived radiotracer [ 11 C]CFN, with and without naloxone blocking. Further research is needed to evaluate the behavioral and clinical relevance of sex differences in naloxone-MOR interactions.