Granzyme B PET Imaging for Assessment of Disease Activity in Inflammatory Bowel Disease.

Developing a noninvasive imaging method to detect immune system activation with a high temporal resolution is key to improving inflammatory bowel disease (IBD) management. In this study, granzyme B (GZMB), typically released from cytotoxic T and natural killer cells, was targeted using PET with 68Ga-NOTA-GZP (where GZP is ß-Ala-Gly-Gly-Ile-Glu-Phe-Asp-CHO) to detect early intestinal inflammation in murine models of colitis. Methods: Bioinformatic analysis was used to assess the potential of GZMB as a biomarker for detecting IBD and predicting response to treatment. Human active and quiescent Crohn disease and ulcerative colitis tissues were stained for GZMB. We used IL-10-/- mice treated with dextran sulfate sodium (DSS) as an IBD model, wild-type C57BL/6J mice as a control, and anti-tumor necrosis factor as therapy. We used a murine GZMB-binding peptide conjugated to a NOTA chelator (NOTA-GZP) labeled with 68Ga as the PET tracer. PET imaging was conducted at 1, 3, and 4 wk after colitis induction to evaluate temporal changes. Results: Bioinformatic analysis showed that GZMB gene expression is significantly upregulated in human ulcerative colitis and Crohn disease compared with the noninflamed bowel by 2.98-fold and 1.92-fold, respectively; its expression is lower by 2.16-fold in treatment responders than in nonresponders. Immunofluorescence staining of human tissues demonstrated a significantly higher GZMB in patients with active than with quiescent IBD (P = 0.032).68Ga-NOTA-GZP PET imaging showed significantly increased bowel uptake in IL-10-/- mice with DSS-induced colitis compared with vehicle-treated IL-10-/- mice (SUVmean, 0.75 vs. 0.24; P < 0.001) and both vehicle- and DSS-treated wild-type mice (SUVmean, 0.26 and 0.37; P < 0.001). In the IL-10-/- DSS-induced colitis model, the bowel PET probe uptake decreased in response to treatment with tumor necrosis factor-α (SUVmean, 0.32; P < 0.001). There was a 4-fold increase in colonic uptake of 68Ga-NOTA-GZP in the colitis model compared with the control 1 wk after colitis induction. The uptake gradually decreased to approximately 2-fold by 4 wk after IBD induction; however, the inflamed bowel uptake remained significantly higher than control at all time points (week 4 SUVmean, 0.23 vs. 0.08; P = 0.001). Conclusion: GZMB is a promising biomarker to detect active IBD and predict response to treatment. This study provides compelling evidence to translate GZMB PET for imaging IBD activity in clinical settings.

Allysine-Targeted Molecular MRI Enables Early Prediction of Chemotherapy Response in Pancreatic Cancer.

Neoadjuvant therapy (NAT) is routinely used in pancreatic ductal adenocarcinoma (PDAC), but not all tumors respond to this treatment. Current clinical imaging techniques are not able to precisely evaluate and predict the response to neoadjuvant therapies over several weeks. A strong fibrotic reaction is a hallmark of a positive response, and during fibrogenesis allysine residues are formed on collagen proteins by the action of lysyl oxidases (LOX). Here we report the application of an allysine-targeted molecular magnetic resonance imaging (MRI) probe, MnL3, to provide an early, noninvasive assessment of treatment response in PDAC. Allysine increased 2- to 3-fold after one dose of NAT with FOLFIRINOX in sensitive human PDAC xenografts in mice. Molecular MRI with MnL3 could specifically detect and quantify fibrogenesis in PDAC xenografts. Comparing the MnL3 signal before and 3 days after one dose of FOLFIRINOX predicted subsequent treatment response. The MnL3 tumor signal increased by 70% from day 0 to day 3 in mice that responded to subsequent doses of FOLFIRINOX, while no signal increase was observed in FOLFIRINOX-resistant tumors. This study indicates the promise of allysine-targeted molecular MRI as a noninvasive tool to predict chemotherapy outcomes.

Noninvasive Quantification of Radiation-Induced Lung Injury Using a Targeted Molecular Imaging Probe.

PURPOSE: Radiation-induced lung injury (RILI) is a progressive inflammatory process seen after irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management. Here, we sought to noninvasively quantify RILI using a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI. METHODS AND MATERIALS: Using a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe, to characterize the development of RILI and to assess disease mitigation after losartan treatment. The human analog probe 68Ga-CBP8, targeting type 1 collagen, was tested on excised human lung tissue containing RILI and was quantified via autoradiography. 68Ga-CBP8 positron emission tomography was used to assess RILI in vivo in 6 human subjects. RESULTS: Murine models demonstrated that probe signal correlated with progressive RILI severity over 6 months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding versus unirradiated control tissue, and 68Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant 68Ga-CBP8 uptake in areas of RILI and minimal background uptake. CONCLUSIONS: These findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI.

DNA Damage by Radiopharmaceuticals and Mechanisms of Cellular Repair.

DNA is an organic molecule that is highly vulnerable to chemical alterations and breaks caused by both internal and external factors. Cells possess complex and advanced mechanisms, including DNA repair, damage tolerance, cell cycle checkpoints, and cell death pathways, which together minimize the potentially harmful effects of DNA damage. However, in cancer cells, the normal DNA damage tolerance and response processes are disrupted or deregulated. This results in increased mutagenesis and genomic instability within the cancer cells, a known driver of cancer progression and therapeutic resistance. On the other hand, the inherent instability of the genome in rapidly dividing cancer cells can be exploited as a tool to kill by imposing DNA damage with radiopharmaceuticals. As the field of targeted radiopharmaceutical therapy (RPT) is rapidly growing in oncology, it is crucial to have a deep understanding of the impact of systemic radiation delivery by radiopharmaceuticals on the DNA of tumors and healthy tissues. The distribution and activation of DNA damage and repair pathways caused by RPT can be different based on the characteristics of the radioisotope and molecular target. Here we provide a comprehensive discussion of the biological effects of RPTs, with the main focus on the role of varying radioisotopes in inducing direct and indirect DNA damage and activating DNA repair pathways.

Noninvasive Quantification of Radiation-Induced Lung Injury using a Targeted Molecular Imaging Probe.

Rationale: Radiation-induced lung injury (RILI) is a progressive inflammatory process commonly seen following irradiation for lung cancer. The disease can be insidious, often characterized by acute pneumonitis followed by chronic fibrosis with significant associated morbidity. No therapies are approved for RILI, and accurate disease quantification is a major barrier to improved management. Objective: To noninvasively quantify RILI, utilizing a molecular imaging probe that specifically targets type 1 collagen in mouse models and patients with confirmed RILI. Methods: Using a murine model of lung radiation, mice were imaged with EP-3533, a type 1 collagen probe to characterize the development of RILI and to assess disease mitigation following losartan treatment. The human analog probe targeted against type 1 collagen, 68Ga-CBP8, was tested on excised human lung tissue containing RILI and quantified via autoradiography. Finally, 68Ga-CBP8 PET was used to assess RILI in vivo in six human subjects. Results: Murine models demonstrated that probe signal correlated with progressive RILI severity over six-months. The probe was sensitive to mitigation of RILI by losartan. Excised human lung tissue with RILI had increased binding vs unirradiated control tissue and 68Ga-CBP8 uptake correlated with collagen proportional area. Human imaging revealed significant 68Ga-CBP8 uptake in areas of RILI and minimal background uptake. Conclusions: These findings support the ability of a molecular imaging probe targeted at type 1 collagen to detect RILI in preclinical models and human disease, suggesting a role for targeted molecular imaging of collagen in the assessment of RILI.Clinical trial registered with www.clinicaltrials.gov (NCT04485286, NCT03535545).

Addition of Peptide Receptor Radiotherapy to Immune Checkpoint Inhibition Therapy Improves Outcomes in Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are often diagnosed in advanced stages. Despite the advances in treatment approaches, including somatostatin analogs and peptide receptor radionuclide therapy (PRRT), these patients have no curative treatment option. Moreover, immunotherapy often yields modest results in NETs. We investigated whether combining PRRT using [177Lu]DOTATATE and immune checkpoint inhibition therapy improves treatment response in NETs. Methods: A gastroenteropancreatic NET model was generated by subcutaneous implantation of human QGP-1 cells in immune-reconstituted NOD.Cg-Prkdcscid Il2rgtm1Wjl /SzJ mice engrafted with human peripheral blood mononuclear cells (n = 96). Mice were randomly assigned to receive pembrolizumab (anti-PD1), [177Lu]DOTATATE (PRRT), simultaneous anti-PD1 and PRRT (S-PRRT), anti-PD1 on day 0 followed by PRRT on day 3 (delayed PRRT [D-PRRT]), PRRT on day 0 followed by anti-PD1 (early PRRT [E-PRRT]), or vehicle as control (n = 12/group). Human granzyme-B-specific [68Ga]NOTA-hGZP PET/MRI was performed before and 6 d after treatment initiation, as an indicator of T-cell activation. Response to treatment was based on tumor growth over 21 d and on histologic analyses of extracted tissues on flow cytometry for T cells, hematoxylin and eosin staining, and immunohistochemical staining. Results: [68Ga]NOTA-hGZP PET/MRI showed significantly increased uptake in tumors treated with E-PRRT, S-PRRT, and anti-PD1 on day 6 compared with baseline (SUVmax: 3.36 ± 0.42 vs. 0.73 ± 0.23; 2.36 ± 0.45 vs. 0.76 ± 0.30; 2.20 ± 0.20 vs. 0.72 ± 0.28, respectively; P < 0.001), whereas no significant change was seen in PET parameters in the D-PRRT, PRRT, or vehicle groups (P > 0.05). Ex vivo analyses confirmed the PET results showing the highest granzyme-B levels and T cells (specifically CD8-positive effector T cells) in the E-PRRT group, followed by the S-PRRT and anti-PD1 groups. Tumor growth follow-up showed the most significant tumor size reduction in the E-PRRT group (baseline to day 21, 205.00 ± 30.70 mm3 vs. 78.00 ± 11.75 mm3; P = 0.0074). Tumors showed less growth reduction in the PRRT, D-PRRT, and S-PRRT groups than in the E-PRRT group (P < 0.0001). The vehicle- and anti-PD-1-treated tumors showed continued growth. Conclusion: Combination of PRRT and anti-PD1 shows the most robust inflammatory response to NETs and a better overall outcome than immune checkpoint inhibition or PRRT alone. The most effective regimen is PRRT preceding anti-PD1 administration by several days.

Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) Versus the Standard of Care Imaging in the Diagnosis of Peritoneal Carcinomatosis.

OBJECTIVE: To compare positron emission tomography (PET)/magnetic resonance imaging (MRI) to the standard of care imaging (SCI) for the diagnosis of peritoneal carcinomatosis (PC) in primary abdominopelvic malignancies. SUMMARY BACKGROUND DATA: Identifying PC impacts prognosis and management of multiple cancer types. METHODS: Adult subjects were prospectively and consecutively enrolled from April 2019 to January 2021. Inclusion criteria were: 1) acquisition of whole-body contrast-enhanced (CE) 18F-fluorodeoxyglucose PET/MRI, 2) pathologically confirmed primary abdominopelvic malignancies. Exclusion criteria were: 1) greater than 4 weeks interval between SCI and PET/MRI, 2) unavailable follow-up. SCI consisted of whole-body CE PET/computed tomography (CT) with diagnostic quality CT, and/or CE-CT of the abdomen and pelvis, and/or CE-MRI of the abdomen±pelvis. If available, pathology or surgical findings served as the reference standard, otherwise, imaging followup was used. When SCI and PET/MRI results disagreed, medical records were checked for management changes. Follow-up data were collected until August 2021. RESULTS: One hundred sixty-four subjects were included, 85 (52%) were female, and the median age was 60 years (interquartile range 50-69). At a subject level, PET/MRI had higher sensitivity (0.97, 95% CI 0.86-1.00) than SCI (0.54, 95% CI 0.37-0.71), P < 0.001, without a difference in specificity, of 0.95 (95% CI 0.90-0.98) for PET/MRI and 0.98 (95% CI 0.93-1.00) for SCI, P » 0.250. PET/MRI and SCI results disagreed in 19 cases. In 5/19 (26%) of the discordant cases, PET/MRI findings consistent with PC missed on SCI led to management changes. CONCLUSION: PET/MRI improves detection of PC compared with SCI which frequently changes management.

HER3 PET Imaging Predicts Response to Pan Receptor Tyrosine Kinase Inhibition Therapy in Gastric Cancer.

PURPOSE: New generation of receptor tyrosine kinase inhibitors (RTKIs) have shown to improve survival in many solid tumors. However, an imaging biomarker is needed for patient selection and prediction of treatment response. This study evaluates the use of quantitative changes of HER3 on 68 Ga-NOTA-HER3P1 PET/MRI for prediction of early response to pan-RTKIs in gastric cancer (GCa). PROCEDURES: GCa cell lines were evaluated for expression of RTKs, and downstream signaling pathways (AKT and MAPK). Cell viability was assessed following 24-72 h of treatment with 0.01-1 µmol/L of afatinib, a pan-RTKI. HER3-expressing afatinib-sensitive (NCI-N87) and resistant cells (SNU16) were selected for evaluation of changes in RTKs expression and downstream pathways, with 24-72 h of 0.1 µmol/L afatinib treatment. 68 Ga-NOTA-HER3P1 PET/MRI was performed in subcutaneous NCI-N87 and SNU16 xenografts (nu:nu, n = 12/group) at baseline and 4 days after afatinib treatment (10 mg/kg, PO, daily). Temporal changes in PET measures were correlated to HER3 expression in tumors, tumor growth rate, and treatment response. RESULTS: With afatinib therapy, NCI-N87 cells showed increased total HER3 expression, and reduction of other RTKs and downstream nodes within 72 h, while SNU16 cells showed no significant change in total HER3 and downstream nodes. 68 Ga-HER3P1 PET/MRI showed increased uptake in NCI-N87 and no significant change in SNU16 tumors (day 4 vs. baseline SUVmean: 3.8 ± 0.7 vs. 1.6 ± 0.6, p < 0.05 in NCI-N87, and 1.5 ± 0.7 vs. 1.7 ± 0.7, p > 0.05 in SNU16). These findings were in concordance with HER3 expression in histopathological analyses and tumor growth over 3 weeks of treatment (mean tumor volume in treated vs. control: 11 ± 17 mm3 vs. 293 ± 79 mm3, p < 0.001 in NCI-N87, and 238 ± 91 mm3 vs. 282 ± 35 mm3, p > 0.05 in SNU16). CONCLUSIONS: Quantitative changes in HER3 PET could be used to predict response to pan-RTKI within few days after initiation of treatment and can help with personalizing GCa management.

Hyperpolarized [1-13C]Pyruvate Magnetic Resonance Spectroscopic Imaging for Evaluation of Early Response to Tyrosine Kinase Inhibition Therapy in Gastric Cancer.

PURPOSE: To evaluate the use of hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopic imaging (HP-13C MRSI) for quantitative measurement of early changes in glycolytic metabolism and its ability to predict response to pan-tyrosine kinase inhibitor (Pan-TKI) therapy in gastric cancer (GCa). PROCEDURES: Pan-TKI afatinib-sensitive NCI-N87 and resistant SNU16 human GCa cells were assessed for GLUT1, hexokinase-II (HKII), lactate dehydrogenase (LDHA), phosphorylated AKT (pAKT), and phosphorylated MAPK (pMAPK) at 0-72 h of treatment with 0.1 µM afatinib. Subcutaneous NCI-N87 tumor-bearing nude mice underwent [18F]FDG PET/MRI and HP-13C MRSI at baseline and 4 days after treatment with afatinib 10 mg/kg/day or vehicle (n = 10/group). Changes in PET and HP-13C MRSI metabolic parameters were compared between the two groups. Imaging findings were correlated with tumor growth and histopathology over 3 weeks of treatment. RESULTS: In vitro analysis showed a continuous decrease in LDHA, pAKT, and pMAPK in NCI-N87 compared to SNU16 cells within 72 h of treatment with afatinib, without a significant change in GLUT1 and HKII in either cell type. [18F]FDG PET of NCI-N87 tumors showed no significant change in PET measures at baseline and day 4 of treatment in either treatment group (SUVmean day 4/day 0: 2.7 ± 0.42/2.34 ± 0.38, p = 0.57 in the treated group vs. 1.73 ± 0.66/2.24 ± 0.43, p = 0.4 in the control group). HP-13C MRSI demonstrated significantly decreased lactate-to-pyruvate ratio (L/P) in treated tumors (L/P day 4/day 0: 0.83 ± 0.30/1.10 ± 0.20, p = 0.012 vs. 0.94 ± 0.20/0.98 ± 0.30, p = 0.75, in the treated vs. control group, respectively). Response to afatinib was confirmed with decreased tumor size over 3 weeks (11.10 ± 16.50 vs. 293.00 ± 79.30 mm3, p < 0.001, treated group vs. control group, respectively) and histopathologic evaluation. CONCLUSIONS: HP-13C MRSI is a more representative biomarker of early metabolic changes in response to pan-TKI in GCa than [18F]FDG PET and could be used for early prediction of response to targeted therapies.

Dispelling myths: The case for women in radiology and radiation oncology.

Common misconceptions about radiology and radiation oncology exist and may dissuade women from pursuing these specialties. The American Association for Women in Radiology (AAWR) Medical Student Outreach Subcommittee began a multi-year social media campaign aimed at addressing these myths. Here, we outline several myths presented in this social media campaign and provide a combination of literature review and experts' opinions to deconstruct and dispel them.

PET/MRI and PET/CT Radiomics in Primary Cervical Cancer: A Pilot Study on the Correlation of Pelvic PET, MRI, and CT Derived Image Features.

PURPOSE: To evaluate the correlation of radiomic features in pelvic [2-deoxy-2-18F]fluoro-D-glucose positron emission tomography/magnetic resonance imaging and computed tomography ([18F]FDG PET/MRI and [18F]FDG PET/CT) in patients with primary cervical cancer (CCa). PROCEDURES: Nineteen patients with histologically confirmed primary squamous cell carcinoma of the cervix underwent same-day [18F]FDG PET/MRI and PET/CT. Two nuclear medicine physicians performed a consensus reading in random order. Free-hand regions of interest covering the primary cervical tumors were drawn on PET, contrast-enhanced pelvic CT, and pelvic MR (T2 weighted and ADC) images. Several basic imaging features, standard uptake values (SUVmean, SUVmax, and SUVpeak), total lesion glycolysis (TLG), metabolic tumor volume (MTV), and more advanced texture analysis features were calculated. Pearson's correlation test was used to assess the correlation between each pair of features. Features were compared between local and metastatic tumors, and their role in predicting metastasis was evaluated by receiver operating characteristic curves. RESULTS: For a total of 101 extracted features, 1104/5050 pairs of features showed a significant correlation (ρ ≥ 0.70, p < 0.05). There was a strong correlation between 190/484 PET pairs of features from PET/MRI and PET/CT, 91/418 pairs of CT and PET from PET/CT, 79/418 pairs of T2 and PET from PET/MRI, and 50/418 pairs of ADC and PET from PET/MRI. Significant difference was seen between eight features in local and metastatic tumors including MTV, TLG, and entropy on PET from PET/CT; MTV and TLG on PET from PET/MRI; compactness and entropy on T2; and entropy on ADC images. CONCLUSIONS: We demonstrated strong correlation of many extracted radiomic features between PET/MRI and PET/CT. Eight radiomic features calculated on PET/CT and PET/MRI were significantly different between local and metastatic CCa. This study paves the way for future studies to evaluate the diagnostic and predictive potential of radiomics that could guide clinicians toward personalized patients care.

Academic Leadership: Harnessing the Culture of Inclusion in Nuclear Medicine and Radiology.

ABSTRACT: Culture of inclusion is of utmost need in today's practice of radiology and nuclear medicine. This article briefly describes the importance of establishing and enriching the culture of embracing different talents, perspectives, and expertise with consideration of differences in sex, ethnic, color, and socioeconomic background toward building high-performance research and clinical practice teams in academic nuclear medicine and radiology.

Challenges faced by women in radiology during the pandemic - A summary of the AAWR Women's Caucus at the ACR 2020 annual meeting.

The COVID-19 pandemic has dramatically altered the professional and personal lives of radiologists and radiation oncologists. This article summarizes the 2020 American Association for Women in Radiology (AAWR) Women's Caucus at the American College of Radiology (ACR) Annual Meeting. The caucus focused on the major challenges that women in radiology have faced during the pandemic.

PET/MRI Radiomics in Rectal Cancer: a Pilot Study on the Correlation Between PET- and MRI-Derived Image Features with a Clinical Interpretation.

PURPOSE: The aim of this study was to explore possible correlations among different imaging features from 2-deoxy-2-[18F]fluoro-D-Glucose positron emission tomography/magnetic resonance imaging (PET/MRI) in rectal cancer (RC). PROCEDURES: RC patients who underwent PET/MRI were enrolled. A region of interest (ROI) was drawn around each primary RC on PET/MRI images (PET, pelvic axial T2w, and apparent diffusion coefficient maps (ADC)). Multiple imaging features were assessed, and Pearson's correlation was used to explore possible correlations among them. RESULTS: A total of 13 patients were included, mean age 56.1 years old, 6 females. A strong inverse correlation was observed between SUVpeak and ADCmean values, MTV and T2 sphericity, MTV and ADC sphericity, MTV and T2 entropy, and TLG and ADC sphericity. There was also strong direct correlation between PET entropy and ADC sphericity. CONCLUSIONS: In conclusion, several clinically relevant correlations were observed between PET and MRI imaging features. These findings show how the use of both modalities provides complementary information.

Optical imaging with a novel cathepsin-activatable probe for enhanced detection of colorectal cancer.

We evaluated a cysteine cathepsin-activatable optical imaging probe (LUM015) with improved kinetics relative to larger macromolecules for detection and characterization of colorectal cancer (CRC), and thereby assessed its potential use in fluorescence-guided colonoscopy. We showed that LUM015 is stable in plasma. In-vitro studies demonstrated selectivity of LUM015 for targeting cathepsins; there was robust increase in emitted fluorescence signal from the cathepsin overexpressing HT-29 CRC cells within 1-5 minutes after incubation with LUM015 compared to the cells incubated with combination of LUM015 and a pan-protease inhibitor (as negative control). Biodistribution, differential accumulation of the probe in the tumor and tumor-to-background fluorescence signal ratio of LUM015 were compared to ProSense680, a commercially available protease-activatable optical imaging probe, over 24 hours after intravenous injection of the probes in nude mice with subcutaneously implanted HT-29 tumors. LUM015 showed distinct kinetics compared to ProSense680 with time to peak signal for subcutaneous tumor-to-colon ratio of 3.3±0.3 (mean ± SD) at 4-8 hours compared to 2.9±0.2 at 24 hours, respectively (n=8 for each group). Near-infrared fluorescence imaging and dual channel colonoscopy of the mice with orthotopic colon tumors showed tumor-to-colon ratio of 3.7±0.2 in HT-29 tumors (n=4), 2.8±0.1 in genetically engineered mice with APCKOKrasLSL-G12Dp53flox/flox mutation (n=4), and 4.1±0.1 in mice with APCLoxP/LoxPMsh2LoxP/LoxP mutation (n=4) at 6 hours after LUM015 administration. Immunohistochemistry and laser confocal microscopy of the extracted tumors confirmed high expression of cysteine cathepsins in all colon tumor types tested. Optical imaging with cathepsin-activatable LUM015 in multiple models of CRC highlights its potential for increasing the efficacy of CRC screening and therapeutic procedures.

Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib.

Lorlatinib (PF-06463922) is a next-generation small-molecule inhibitor of the orphan receptor tyrosine kinase c-ros oncogene 1 (ROS1), which has a kinase domain that is physiologically related to anaplastic lymphoma kinase (ALK), and is undergoing Phase I/II clinical trial investigations for non-small cell lung cancers. An early goal is to measure the concentrations of this drug in brain tumour lesions of lung cancer patients, as penetration of the blood-brain barrier is important for optimal therapeutic outcomes. Here we prepare both 11C- and 18F-isotopologues of lorlatinib to determine the biodistribution and whole-body dosimetry assessments by positron emission tomography (PET). Non-traditional radiolabelling strategies are employed to enable an automated multistep 11C-labelling process and an iodonium ylide-based radiofluorination. Carbon-11-labelled lorlatinib is routinely prepared with good radiochemical yields and shows reasonable tumour uptake in rodents. PET imaging in non-human primates confirms that this radiotracer has high brain permeability.