About

Robert H Mach, Ph.D., is the Britton Chance Professor of Radiology at the University of Pennsylvania's Perelman School of Medicine. He serves as the Director of Radiochemistry Research in the Department of Radiology. His research focuses on the development of radiotracers for studying the molecular basis of disease using positron emission tomography (PET). His current projects include imaging dopamine D3 receptors in addiction, alpha synuclein in Parkinson’s disease and other synucleinopathies, and PARP-1 in cancer and CNS disorders. Mach's laboratory also investigates cancer cell biology, notably identifying the role of a ternary complex involving sigma-2 receptor/TMEM97, LDL receptor, and PGRMC1 in cholesterol support for cell proliferation. He has affiliations with graduate groups in Neuroscience and Pharmacology and has contributed to the development of PET radiotracers for neurodegenerative diseases and cancer, with numerous publications in the field.

Research topics

• Nuclear medicine
• Oncology
• Medical physics
• Internal medicine
• Pharmacology
• Medicine

Selected publications

• CCDC 2479819: Experimental Crystal Structure Determination

  Open MIND · 2026-01-28 · 2 citations

  articleOpen access

  An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

  OA PDFDOI

• Associations between Myocardial Susceptibility and Reactive Oxygen Species in the Subacute and Chronic Period of Myocardial Infarction

  Journal of Cardiovascular Magnetic Resonance · 2026-01-01

  articleOpen access
  PublisherDOI

• Autoradiography and preclinical PET studies with radiolabeled asyn-44 and ACI-12589 for imaging α-synuclein

  Journal of Parkinson s Disease · 2026-04-17

  articleOpen access

  Background Parkinson's disease (PD) and multiple system atrophy (MSA) are considered α-synucleinopathies, characterized by the presence of pathological α-synuclein (α-syn) aggregates. A positron emission tomography (PET) tracer for imaging α-syn aggregates in vivo is highly sought after, as disease progression correlates with the accumulation of aggregated α-syn. We recently reported [ 18 F]asyn-44 as a radiotracer for α-syn, worthy of evaluation in higher species, based on in vitro binding data from human brain tissues and in vivo PET imaging studies in rodents. Objective [ 3 H]ACI-12589 is a promising α-syn PET tracer which recently showed binding in MSA patients but appears to have limited utility in other α-synucleinopathies. Objective 1) compare the in vitro binding properties of our lead, [ 3 H]asyn-44, to [ 3 H]ACI-12589; Objective 2) evaluate [ 18 F]asyn-44 and [ 18 F]ACI-12589 kinetics by in vivo PET imaging in normal rodents; Objective 3) assess pharmacokinetic properties and metabolism of [ 18 F]asyn-44 in normal pig and non-human primate (NHP). Methods In vitro autoradiography with [ 3 H]asyn-44 and [ 3 H]ACI-12589 was performed to compare radiotracer binding in PD, MSA, Alzheimer's disease and healthy control post-mortem brain tissue. Additionally, preclinical PET imaging was performed in rats with [ 18 F]ACI-12589 to compare with our previously reported [ 18 F]asyn-44 data. Further evaluation of [ 18 F]asyn-44 in higher species was carried out by preclinical PET imaging in pig and NHP with metabolite analysis. Liver microsome assays and mass spectrometry were performed to identify the metabolites formed in NHP. Results [ 3 H]Asyn-44 and [ 3 H]ACI-12589 displayed different binding properties in both PD and MSA tissue, suggesting that the tracers target different binding sites and asyn-44 might therefore be more suited for PD imaging. In the pig, [ 18 F]asyn-44 readily entered the brain and no brain penetrant metabolites were observed in arterial blood samples. In the NHP, [ 18 F]asyn-44 readily entered the brain but was rapidly metabolized. Radiolabeled metabolites of asyn-44 were proposed and will be considered in the design of future derivatives. Conclusions Species differences in metabolism of [ 18 F]asyn-44 are observed between pig and NHP, and do not support the further translation of [ 18 F]asyn-44. Additionally, autoradiography with [ 3 H]asyn-44 revealed low signal specificity and high non-displaceable binding. We report evidence for off-target binding of [ 3 H]ACI-12589 to amyloid-β plaques. The limitations of both [ 3 H]asyn-44 and [ 3 H]ACI-12589 reported here support the development of additional derivatives and structural scaffolds of asyn-44 with the potential to improve radiotracer specificity and selectivity towards α-syn.

  PublisherDOI

• Machine learning prediction of multiple distinct high-affinity chemotypes for α-synuclein fibrils

  Chemical Communications · 2026-01-01

  articleOpen access

  To identify new ligands for positron emission tomography imaging of α-synuclein aggregates, we developed a machine learning model trained on <300 binding measurements. We used scaffold-guided curation to select a 30 compound prospective set from a 140-million-member library. Experimental validation yielded five high-affinity binders, showing robust generalization for ligand discovery.

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• Discovery of N-(6-Methoxypyridin-3-yl)quinoline-2-amine Derivatives for Imaging Aggregated α-Synuclein in Parkinson’s Disease with Positron Emission Tomography

  Cells · 2025-07-18 · 1 citations

  articleOpen access

  The fibrillary aggregation of α-synuclein is a hallmark of Parkinson’s disease (PD) and a potential target for diagnostics and therapeutics. Although substantial effort has been devoted to the development of positron emission tomography (PET) probes for detecting α-synuclein aggregates, no clinically suitable tracer has been reported. The design and synthesis of 43 new N-(6-methoxypyridin-3-yl)quinolin-2-amine derivatives and an evaluation of their α-synuclein binding affinity is reported here. Compounds 7f, 7j, and 8i exhibited high affinity for α-synuclein and were selected for 11C, 18F, 125I, or 3H radiolabeling. A photoaffinity variant, TZ-CLX, structurally related to 7j and 8i, demonstrated preferential binding to the C-terminal region of α-synuclein fibrils. PET brain imaging studies using [11C]7f, [18F]7j, and [11C]8i in non-human primates indicated that these three α-synuclein PET tracers penetrated the blood–brain barrier. Both [11C]7f and [18F]7j showed more favorable brain washout pharmacokinetics than [11C]8i. In vitro binding assays showed that [125I]8i is a very potent α-synuclein radioligand, with Kd values of 5 nM for both PD brain tissues and LBD-amplified fibrils; it is also selective for PD tissues versus AD or control tissues. These results strongly suggest that the PET probes based on the N-(6-methoxypyridin-3-yl)quinoline-2-amine scaffold have potential utility in detecting α-synuclein aggregates in vivo.

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• Optical Redox Imaging of Breast Cancer NADH Redox Status Associated with PGC1α Gene Expression

  Academic Radiology · 2025-12-19

  articleOpen access

  <h3>Rationale and Objectives</h3> Remarkable intratumor heterogeneity of mitochondrial redox state was found in malignant tumors by optical redox imaging (ORI) of reduced nicotinamide adenine dinucleotide (NADH), oxidized flavoproteins (Fp) containing flavin adenine dinucleotide, and the optical redox ratio (ORR = Fp/(NADH + Fp)), with higher and lower ORR corresponding to more oxidative and more reductive redox status, respectively. Our previous reports suggested that ORR can be a biomarker for cancer aggressiveness or risk of progression. Our goal here is to explore the molecular basis of the ORR's biomarker value for breast cancer by investigating the expression and activity of PGC1α, a master regulator of mitochondrial metabolism and cancer progression. <h3>Materials and Methods</h3> Intratumor redox subpopulations were isolated from triple-negative breast cancer (TNBC) MDA-MB-231 mouse xenografts and grouped according to high, medium, and low levels of ORI indices (ORR, Fp, or NADH). Gene expression and associated gene networks were obtained by RNA sequencing and bioinformatics analysis, respectively. PGC1α gene expression was validated by RT-PCR. The role of PGC1α in TNBC progression was further investigated by knocking down PGC1α (validated by western blot and RT-qPCR) in MAD-MB-231 cells and measuring the changes in ORI indices and invasiveness in vitro. <h3>Results</h3> PGC1α was upregulated in the subpopulation with a high ORR compared to that with a medium ORR. A PGC1α associated gene network with 21 differentially expressed genes (DEGs) was also identified, implicating regulation of redox signaling, metabolism, and cancer progression. Important signaling regulating genes SIRT1 and FOXO1 were upregulated, whose activities influence the NAD⁺/NADH ratio or are influenced by the NAD⁺/NADH ratio. Decreased ORR and invasiveness were observed in vitro in PGC1α knockdown MDA-MB-231 cells, supporting the association of higher PGC1α expression with more oxidative redox status. <h3>Conclusion</h3> ORI-based redox subpopulations in TNBC tumors exhibited differential expression of PGC1α gene that was associated with a gene network, providing a possible molecular basis underlying the potential value of ORR as a prognostic biomarker.

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

  medRxiv · 2025-10-08

  preprintOpen access

  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.

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• Quantitative Susceptibility Mapping and R2* of Ischemia-reperfusion Injury and its Relationship with Reactive Oxygen Species Activity

  Proceedings on CD-ROM - International Society for Magnetic Resonance in Medicine. Scientific Meeting and Exhibition/Proceedings of the International Society for Magnetic Resonance in Medicine, Scientific Meeting and Exhibition · 2025-09-16

  article

  Motivation: There is a need for specific imaging of ischemia-reperfusion injury (IRI) as it initiates infarct iron deposition, catalyzing reactive oxygen species (ROS) production and heart failure. Goal(s): Our goal was to assess and image the relationships between susceptibility, R2*, and ROS activity. Approach: Six swine with IRI were imaged to quantify iron using QSM and R2*, and to measure ROS activity. Results: Regions of hemorrhage and infarct had higher susceptibility, R2* and ROS activity compared to remote regions. There was a positive correlation between infarct ROS activity and R2* in the hemorrhage, and between infarct ROS activity and susceptibility in the hemorrhage. Impact: The observed associations between magnetic susceptibility and R2* with ROS activity allows for better understanding of IRI and potential to develop new targeted interventions. This suggests that iron could be a catalyst for ROS production in ischemia-reperfusion injury.

  PublisherDOI

• Abstract A043: Preclinical evaluation of PTT, an At-211-Labeled rucaparib analogue, as a theranostic agent for cancer therapy

  Cancer Research · 2025-09-19

  article

  Abstract Epithelial ovarian cancer (EOC) is generally sensitive to radiation. However, the widespread peritoneal dissemination of advanced EOC renders external beam radiotherapy limited as the required dose has substantial off-target toxicities. Targeted radionuclide therapy can deliver ionizing radiation directly to tumor cells while sparing healthy tissues, offering an alternative strategy to safely exploit the radiosensitivity of these tumors. Our platform is based on the FDA-approved small molecule PARP inhibitor, rucaparib, labeled with 211At for targeted alpha therapy ([211At]Parthanatrace, [211At]PTT). Our prior and ongoing studies support significant anti-tumor efficacy in preclinical neuroblastoma and ovarian cancer models. Here, in vivo studies were performed to evaluate the tolerability of [211At]PTT. C57BL/6 mice (n = 10) were treated intravenously with four fractionated doses of [211At]PTT at the MTD (48 MBq/kg/fraction) over 2 weeks. Generally, mice tolerated the treatment well, with statistically similar weight compared to untreated control mice (n = 6) up to 30 days following treatment, supporting a favorable safety profile. Peripheral blood was collected 5, 13, and 20 days following the last treatment and a subset of mice were euthanized after 30 days for full pathological assessment and additional blood analysis. The data indicated a significant decline in red blood cells (RBCs), white blood cells (WBCs), and hemoglobin in the peripheral blood following treatment. Levels were fully restored by 20 days post treatment. Lymphocyte and platelet counts were similar to untreated mice after 30 days. Additional blood analyses showed statistically similar levels for aspartate aminotransferase (AST), alanine transferase (ALT), bilirubin (BUN), and creatine in mice treated with [211At]PTT compared to untreated controls. Full histological and pathological assessment is ongoing. Subsequent biodistribution studies demonstrated selective tissue uptake of [211At]PTT following a single infusion of 48 MBq/kg, with limited off-target accumulation and rapid clearance from non-target organs. Overall, these findings support the safety of [211At]PTT as a promising candidate for targeted alpha therapy in oncology. Citation Format: Aladdin Riad, Alastair McArthur, Hasan Babazda, David Mankoff, Robert H. Mach, Michael D. Farwell, Sarah B. Gitto. Preclinical evaluation of PTT, an At-211-Labeled rucaparib analogue, as a theranostic agent for cancer therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr A043.

  PublisherDOI

• Radiotracer Competition Binding Experiments with α-Synuclein Fibrils Reveal Insights into Designs for Ligand Specificity

  ChemRxiv · 2025-12-15 · 1 citations

  articleOpen access

  To identify structure activity relationships of ligands competing with the site-specific positron emission tomography probe [3H]BF-2846 in α-synuclein aggregates, we have synthesized and characterized the binding of over 300 compounds, exploring three distinct scaffolds and identifing 30 &lt;10 nM affinity binders.

  PublisherDOI

Recent grants

• NIH Grant R21DA016181

  NIH · $1.7M · 2008

• NIH Grant R41CA077951

  NIH · $100k · 1999

• NIH Grant RC1AG036045

  NIH · $995k · 2012

• NIH Grant R33CA102869

  NIH · $1.3M · 2008

• NIH Grant R21MH081281

  NIH · $417k · 2009

Frequent coauthors

• Robert R. Luedtke

  University of North Texas

  148 shared

• Mehran Makvandi

  106 shared

• Jinbin Xu

  98 shared

• Chia‐Ju Hsieh

  California University of Pennsylvania

  93 shared

• David A. Mankoff

  University of Pennsylvania

  72 shared

• Zhude Tu

  Washington University in St. Louis

  69 shared

• Suwanna Vangveravong

  Washington University in St. Louis

  62 shared

• Robert K. Doot

  CHDI Foundation

  56 shared

Labs

• Radiochemistry Research, Department of Radiology, University of PennsylvaniaPI

Education

• PhD, Medicinal Chemistry

  University at Buffalo

  1985

Awards & honors

• Britton Chance Professor of Radiology
• Nanoluciferase Complementation-based Assay for Monitoring β-…