PET Tracers for Imaging Cardiac Function in Cardio-oncology

Purpose of Review Successful treatment of cancer can be hampered by the attendant risk of cardiotoxicity, manifesting as cardiomyopathy, left ventricle systolic dysfunction and, in some cases, heart failure. This risk can be mitigated if the injury to the heart is detected before the onset to irreversible cardiac impairment. The gold standard for cardiac imaging in cardio-oncology is echocardiography. Despite improvements in the application of this modality, it is not typically sensitive to sub-clinical or early-stage dysfunction. We identify in this review some emerging tracers for detecting incipient cardiotoxicity by positron emission tomography (PET). Recent Findings Vectors labeled with positron-emitting radionuclides (e.g., carbon-11, fluorine-18, gallium-68) are now available to study cardiac function, metabolism, and tissue repair in preclinical models. Many of these probes are highly sensitive to early damage, thereby potentially addressing the limitations of current imaging approaches, and show promise in preliminary clinical evaluations. Summary The overlapping pathophysiology between cardiotoxicity and heart failure significantly expands the number of imaging tools available to cardio-oncology. This is highlighted by the emergence of radiolabeled probes targeting fibroblast activation protein (FAP) for sensitive detection of dysregulated healing process that underpins adverse cardiac remodeling. The growth of PET scanner technology also creates an opportunity for a renaissance in metabolic imaging in cardio-oncology research.

Hyperpolarized 13C-Pyruvate Metabolism as a Surrogate for Tumor Grade and Poor Outcome in Renal Cell Carcinoma—A Proof of Principle Study

Differentiating aggressive clear cell renal cell carcinoma (ccRCC) from indolent lesions is challenging using conventional imaging. This work prospectively compared the metabolic imaging phenotype of renal tumors using carbon-13 MRI following injection of hyperpolarized [1-13C]pyruvate (HP-13C-MRI) and validated these findings with histopathology. Nine patients with treatment-naïve renal tumors (6 ccRCCs, 1 liposarcoma, 1 pheochromocytoma, 1 oncocytoma) underwent pre-operative HP-13C-MRI and conventional proton (1H) MRI. Multi-regional tissue samples were collected using patient-specific 3D-printed tumor molds for spatial registration between imaging and molecular analysis. The apparent exchange rate constant (kPL) between 13C-pyruvate and 13C-lactate was calculated. Immunohistochemistry for the pyruvate transporter (MCT1) from 44 multi-regional samples, as well as associations between MCT1 expression and outcome in the TCGA-KIRC dataset, were investigated. Increasing kPL in ccRCC was correlated with increasing overall tumor grade (ρ = 0.92, p = 0.009) and MCT1 expression (r = 0.89, p = 0.016), with similar results acquired from the multi-regional analysis. Conventional 1H-MRI parameters did not discriminate tumor grades. The correlation between MCT1 and ccRCC grade was confirmed within a TCGA dataset (p < 0.001), where MCT1 expression was a predictor of overall and disease-free survival. In conclusion, metabolic imaging using HP-13C-MRI differentiates tumor aggressiveness in ccRCC and correlates with the expression of MCT1, a predictor of survival. HP-13C-MRI may non-invasively characterize metabolic phenotypes within renal cancer.

Super-resolution vibrational imaging using expansion stimulated Raman scattering microscopy

Stimulated Raman scattering (SRS) microscopy is an emerging technology that provides high chemical specificity for endogenous biomolecules and can circumvent common constraints of fluorescence microscopy including limited capabilities to probe small biomolecules and difficulty resolving many colors simultaneously due to spectral overlap. However, the resolution of SRS microscopy remains governed by the diffraction limit. To overcome this, we describe a new technique called Molecule Anchorable Gel-enabled Nanoscale Imaging of Fluorescence and stImulatEd Raman Scattering microscopy (MAGNIFIERS), that integrates SRS microscopy with expansion microscopy (ExM). ExM is a powerful strategy providing significant improvement in imaging resolution by physical magnification of hydrogel-embedded preserved biological specimens. MAGNIFIERS offers chemical-specific nanoscale imaging with sub-50 nm resolution and has scalable multiplexity when combined with multiplex Raman probes and fluorescent labels. We used MAGNIFIERS to visualize nanoscale features in a label-free manner with C-H vibration of proteins, lipids and DNA in a broad range of biological specimens, from mouse brain, liver and kidney to human lung organoid. In addition, we applied MAGNIFIERS to track nanoscale features of protein synthesis in protein aggregates using metabolic labeling of small metabolites. Finally, we used MAGNIFIERS to demonstrate 8-color nanoscale imaging in an expanded mouse brain section. Overall, MAGNIFIERS is a valuable platform for super-resolution label-free chemical imaging, high-resolution metabolic imaging, and highly multiplexed nanoscale imaging, thus bringing SRS to nanoscopy.

Synthesis and evaluation of radiogallium-labeled long-chain fatty acid derivatives as myocardial metabolic imaging agents

Since long-chain fatty acids work as the primary energy source for the myocardium, radiolabeled long-chain fatty acids play an important role as imaging agents to diagnose metabolic heart dysfunction and heart diseases. With the aim of developing radiogallium-labeled fatty acids, herein four fatty acid-based tracers, [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA, which are [67Ga]Ga-HBED-CC and [67Ga]Ga-DOTA conjugated with pentadecanoic acid (PDA) and 3-methylhexadecanoic acid (MHDA), were synthesized, and their potential for myocardial metabolic imaging was evaluated. Those tracers were found to be chemically stable in 0.1 M phosphate buffered saline. Initial [67Ga]Ga-HBED-CC-PDA, [67Ga]Ga-HBED-CC-MHDA, [67Ga]Ga-DOTA-PDA, and [67Ga]Ga-DOTA-MHDA uptakes in the heart at 0.5 min postinjection were 5.01 ± 0.30%ID/g, 5.74 ± 1.02%ID/g, 5.67 ± 0.22%ID/g, and 5.29 ± 0.10%ID/g, respectively. These values were significantly lower than that of [123I]BMIPP (21.36 ± 2.73%ID/g). For their clinical application as myocardial metabolic imaging agents, further structural modifications are required to increase their uptake in the heart.