Jacob G. Dubroff

Purpose: To examine the relationship between brain mu opioid receptor (MOR) availability and liver activity in opioid use disorder (OUD) patients treated with methadone (MET) or buprenorphine (BUP). Methods: 10 OUD patients, 5 treated with MET and 5 with BUP, as well as 13 healthy controls (HCs) underwent total-body PET [ ¹¹ C]carfentanil (CFN) imaging. MOR availability was quantified using distribution volume ratio (DVR) in key MOR-rich brain regions, and hepatic distribution volume (Vt) was used as an index of systemic tracer pharmacokinetics. Serum drug levels were measured in the OUD patients. Results: Brain MOR availability was significantly lower in the OUD groups relative to HCs (p < 0.001), more so in BUP-treated (mean MOR difference = 39.9 ± 15.9%, Cohen’s d = 3.35) than MET-treated (mean MOR difference = 14.2 ± 9.9%, d = 1.90) patients. Central MOR availability was inversely related to serum drug levels, linearly in MET treated (R2 = 0.83) and logarithmically in BUP-treated (R2 = 0.96), consistent with distinct receptor occupancy dynamics. Hepatic Vt differed across groups (p < 0.003) with levels in both OUD groups lower than in HCs (p < 0.05). In MET-treated patients, hepatic Vt was strongly associated with brain MOR availability (R ² = 0.68), and inversely associated with serum drug levels (R ² = 0.63). This relationship was less pronounced in BUP-treated patients (R ² = 0.30), and absent in HCs. Conclusions: Drug-specific, brain-liver pharmacokinetic profiles were observed in OUD patients treated with MET versus BUP. While MET patients demonstrated coupling between hepatic tracer kinetics and brain receptor occupancy, BUP patients did not. These findings demonstrate that drug-specific brain-body pharmacokinetics may underscore observed clinical differences in opioid agonist effects in OUD.

Background: Mu-opioid receptors (MORs) are expressed throughout the body including in the brain and gastrointestinal (GI) tract. Total-body PET imaging of the brain and GI tract offers a promising approach for cross-sectional in vivo evaluation of the MOR brain-GI axis. However, intestinal motility and bladder filling introduce motion throughout the GI tract over the scan window. Here we establish analysis methodology to account for motion for dynamic imaging of the brain-GI axis, to further characterize peripheral MORs throughout the body and provide a framework for semi-automatic total-body PET modeling. Methods: 4 subjects underwent 90-min dynamic [ ¹¹ C]-carfentanil (cfn) total-body PET acquisitions at baseline, after intravenous naloxone (central antagonist) administration, and after orally administered loperamide (peripheral agonist and P-glycoprotein substrate). Thalamic MOR availability was measured using the Logan reference tissue model. Using CT-based segmentation, the GI tract was subdivided into anatomical segments, in addition to other peripheral organs (e.g., liver, psoas muscle). Frame-by-frame semi-automatic motion correction was performed with three distinct reference frames (11-14 min post-injection, p.i., 35-40 min p.i., and 85-90 min p.i.). The performance of these three were compared to manual correction. Compartment modeling and Logan graphical analysis were performed to estimate relevant kinetic parameters (K1, VT, VTLogan). Results: Across the 4 subjects and regions, kinetic parameter estimates were highly correlated (r>0.7) for K1, VT and VT Logan when comparing semi-automatic (reference frame at 35-40 min p.i.) and manual correction. With semi-automatic motion correction, graphical-based estimation of VTLogan in the gastrointestinal tract was significantly decreased with loperamide relative to baseline (p11 C]-cfn total-body PET, pharmacologic perturbations of MOR brain-GI axis can be quantitatively characterized, reducing the burden of image analysis for these studies.

Purpose: Examine the relationship between brain mu opioid receptor (MOR) availability and liver activity in opioid use disorder (OUD) patients treated with methadone (MET) or buprenorphine (BUP). Methods: 10 OUD patients, 5 treated with MET and 5 with BUP, as well as 13 healthy controls (HCs) underwent total-body PET [ ¹¹ C]carfentanil (CFN) imaging. MOR availability was quantified via distribution volume ratio in key MOR-rich brain regions, and hepatic distribution volume (Vt) was used as an index of systemic tracer pharmacokinetics. Serum drug levels were measured in the OUD patients. Results: MOR brain availability was significantly lower in the OUD groups relative to HCs (pd =3.35) than MET-treated (mean MOR difference=14.2±9.9%, d =1.90) patients. Central MOR availability was inversely related to serum drug levels, linearly in MET treated (R²=0.83) and logarithmically in BUP treated (R²=0.96), consistent with distinct receptor occupancy dynamics. Hepatic Vt differed across groups (p2 =0.68) across serum drug levels in MET patients (R ² =0.63). This relationship was decoupled of this relationship in BUP patients (R ² =0.30), and absent in HCs. Conclusions: Drug-specific, brain-liver pharmacokinetic profiles were observed in OUD patients treated with MET versus BUP. While MET patients demonstrated coupling between hepatic tracer kinetics and brain receptor occupancy, BUP patients did not. These findings demonstrate that drug-specific brain-body pharmacokinetics may underscore observed clinical differences in opioid agonist effects in OUD.

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. Methods: 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. 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 < 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. Conclusion: [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. Visual Abstract

Purpose: Long-axial field-of-view PET scanners capture multi-organ tracer distribution with high sensitivity, enabling lower dose dynamic protocols and dual-tracer imaging for comprehensive disease characterization. However, reducing dose may compromise data quality and time-activity curve (TAC) fitting, leading to higher bias in kinetic parameters. Parametric imaging poses further challenges due to noise amplification in voxel-based modelling. We explore the potential of deep learning denoising (DL-DN) to improve quantification for low-dose dynamic PET. Methods: Using 16 [¹⁸F]FDG PET studies from the PennPET Explorer, we trained a DL framework on 10-min images from late-phase uptake (static data) that were sub-sampled from 1/2 to 1/300 of the counts. This model was used to denoise early-to-late dynamic frame images. Its impact on quantification was evaluated using compartmental modelling and voxel-based graphical analysis for parametric imaging for single- and dual-tracer dynamic studies with [¹⁸F]FDG and [¹⁸F]FGln at original (injected) and reduced (sub-sampled) doses. Quantification differences were evaluated for the area under the curve of TACs, K_i for [¹⁸F]FDG and V_T for [¹⁸F]FGln, and parametric images. Results: DL-DN consistently improved image quality across all dynamic frames, systematically enhancing TAC consistency and reducing tissue-dependent bias and variability in K_i and V_T down to 40 MBq doses. DL-DN preserved tumor heterogeneity in Logan V_T images and delineation of high-flux regions in Patlak K_i maps. In a /[¹⁸F]FDG dual-tracer study, bias trends aligned with single-tracer results but showed reduced accuracy for [¹⁸F]FGln in breast lesions at very low doses (4 MBq). Conclusion: This study demonstrates that applying DL-DN trained on static [¹⁸F]FDG PET images to dynamic [¹⁸F]FDG and [¹⁸F]FGln PET can permit significantly reduced doses, preserving accurate FDG K_i and FGln V_T measurements, and enhancing parametric image quality. DL-DN shows promise for improving dynamic PET quantification at reduced doses, including novel dual-tracer studies.

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 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.

Background and Significance: Positron Emission Tomography (PET) using fluorodeoxyglucose (FDG-PET) is a standard imaging modality for detecting areas of hypometabolism associated with the seizure onset zone (SOZ) in temporal lobe epilepsy (TLE). However, FDG-PET is costly and involves the use of a radioactive tracer. Arterial Spin Labeling (ASL) offers an MRI-based quantification of cerebral blood flow (CBF) that could also help localize the SOZ, but its performance in doing so, relative to FDG-PET, is limited. In this study, we seek to improve ASL’s diagnostic performance by developing a deep learning framework for synthesizing FDG-PET-like images from ASL and structural MRI inputs. Methods: We included 68 epilepsy patients, out of which 36 had well lateralized TLE. We compared the coupling between FDG-PET and ASL CBF values in different brain regions, as well as the asymmetry of these values across the brain. We additionally assessed each modality’s ability to lateralize the SOZ across brain regions. Using our paired PET-ASL data, we developed FlowGAN, a generative adversarial neural network (GAN) that synthesizes PET-like images from ASL and T1-weighted MRI inputs. We tested our synthetic PET images against the actual PET images of subjects to assess their ability to reproduce clinically meaningful hypometabolism and asymmetries in TLE. Results: We found variable coupling between PET and ASL CBF values across brain regions. PET and ASL had high coupling in neocortical temporal and frontal brain regions (Spearman’s r > 0.30, p < 0.05) but low coupling in mesial temporal structures (Spearman’s r < 0.30, p > 0.05). Both whole brain PET and ASL CBF asymmetry values provided good separability between left and right TLE subjects, but PET (AUC = 0.96, 95% CI: [0.88, 1.00]) outperformed ASL (AUC = 0.81; 95% CI: [0.65, 0.96]). FlowGAN-generated images demonstrated high structural similarity to actual PET images (SSIM = 0.85). Globally, asymmetry values were better correlated between synthetic PET and original PET than between ASL CBF and original PET, with a mean correlation increase of 0.15 (95% CI: [0.07, 0.24], p d = 0.91). Furthermore, regions that had poor ASL-PET correlation (e.g. mesial temporal structures) showed the greatest improvement with synthetic PET images. Conclusions: FlowGAN improves ASL’s diagnostic performance, generating synthetic PET images that closely mimic actual FDG-PET in depicting hypometabolism associated with TLE. This approach could improve non-invasive SOZ localization, offering a promising tool for epilepsy presurgical assessment. It potentially broadens the applicability of ASL in clinical practice and could reduce reliance on FDG-PET for epilepsy and other neurological disorders.

Acute alcohol intake decreases brain glucose metabolism and increases brain uptake of acetate, a metabolite of alcohol. This shift in energy utilization persists beyond acute intoxication in individuals with alcohol use disorder (AUD), and may contribute to alcohol craving. We recently found that ketone therapies decrease alcohol withdrawal and alcohol craving in AUD. Here, we studied the effects of a single-dose ketone ester (KE) supplement on brain energy metabolism and alcohol craving. Five AUD and five healthy control (HC) participants underwent two ¹⁸ F-fluorodeoxyglucose positron emission tomography (PET) scans, after consumption of 395 mg/kg KE or without (baseline), in randomized order. In the AUD group, KE reduced alcohol craving scores compared to baseline. KE decreased blood glucose levels and elevated blood β-hydroxybutyrate (BHB) levels compared to baseline in both groups. Whole-brain voxel-wise maps of the cerebral metabolic rate of glucose (CMRglc) decreased by 17% in both groups, with the largest KE-induced CMRglc reductions in the frontal, occipital, and cingulate cortices, hippocampus, amygdala, and insula. There were no group differences between AUD and HC in blood or FDG measures, and no correlations between reductions in craving with CMRglc. Cingulate BHB levels, as assessed with ¹ H-magnetic resonance spectroscopy in 5 participant with AUD, increased 3-fold with KE compared to baseleline. In sum, administration of a single dose of KE rapidly shifted brain energetics from glucose to ketone metabolism in HC and AUD. KE also reduced ratings of alcohol craving, demonstrating its potential clinical effectiveness for supporting brain health and alcohol craving in AUD.