Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) has been developed and employed in multiple clinical imaging research centers worldwide. Selective radiofrequency (RF) saturation pulses with standard 2D and 3D MRI acquisition schemes are now routinely performed, and CEST MRI can produce semiquantitative results using magnetization transfer ratio asymmetry (MTRasym) analysis while accounting for B0 inhomogeneity. Faster clinical CEST MRI acquisition methods and more quantitative acquisition and analysis routines are under development. Endogenous biomolecules with amide, amine, and hydroxyl groups have been detected during clinical CEST MRI studies, and exogenous CEST agents have also been administered to patients. These CEST MRI tools show promise for contributing to assessments of cerebral ischemia, neurological disorders, lymphedema, osteoarthritis, muscle physiology, and solid tumors. This review summarizes the salient features of clinical CEST MRI protocols and critically evaluates the utility of CEST MRI for these clinical imaging applications. Level of Evidence: 5 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:11–27.

Self-assembled nanoparticles of triblock copolymers incorporating a NIR-emitting fluorophore and folic acid specifically label folate receptor-positive cells.

Acidosis is a useful biomarker for tumor diagnoses and for evaluating early response to anti-cancer treatments. Despite these useful applications, there are few methods for non-invasively measuring tumor extracellular pH, and none are routinely used in clinics. Responsive MRI contrast agents have been developed, and they undergo a change in MRI signal with pH. However, these signal changes are concentration-dependent, and it is difficult to accurately measure the concentration of an MRI contrast agent in vivo. PET/MRI provides a unique opportunity to overcome this concentration dependence issue by using the PET component to report on the concentration of the pH-responsive MRI agent. Herein, we synthesized PET/MRI co-agents based on the design of a pH-dependent MRI agent, and we have correlated pH with the r1 relaxivity of the MRI co-agent. We have also developed a procedure that uses PET radioactivity measurements and MRI R1 relaxation rate measurements to determine the r1 relaxivity of the MRI co-agent, which can then be used to estimate pH. This simultaneous PET/MRI procedure accurately measured pH in solution, with a precision that depended on the concentration of the MRI co-agent. We used our procedure to measure extracellular pH in a subcutaneous flank model of MIA PaCa-2 pancreatic cancer. Although the PET co-agents were stable in serum, post-imaging studies showed evidence that the PET co-agents were degraded in vivo. These results showed that tumor acidosis can be evaluated with simultaneous PET/MRI, although improvements are needed to more precisely measure MRI R1 relaxation rates, and ensure the in vivo stability of the agents.

Bruton’s tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases. To aid in the discovery and development of BTK inhibitors and improve clinical diagnoses, we have developed a positron emission tomography (PET) radiotracer based on a selective BTK inhibitor, remibrutinib. [18F]PTBTK3 is an aromatic, 18F-labeled tracer that was synthesized in 3 steps with a 14.8 ± 2.4% decay-corrected radiochemical yield and ≥99% radiochemical purity. The cellular uptake of [18F]PTBTK3 was blocked up to 97% in JeKo-1 cells using remibrutinib or non-radioactive PTBTK3. [18F]PTBTK3 exhibited renal and hepatobiliary clearance in NOD SCID (non-obese diabetic/​severe combined immunodeficiency) mice, and the tumor uptake of [18F]PTBTK3 in BTK-positive JeKo-1 xenografts (1.23 ± 0.30% ID/cc) was significantly greater at 60 min post injection compared to the tumor uptake in BTK-negative U87MG xenografts (0.41 ± 0.11% ID/cc). In the JeKo-1 xenografts, tumor uptake was blocked up to 62% by remibrutinib, indicating the BTK-dependent uptake of [18F]PTBTK3 in tumors.