Epichaperome-targeted myocardial imaging by ¹²⁴I-PU-H71 PET

Background: The small molecule radiotracer ¹²⁴I-PU-H71 is an imaging biomarker of epichaperome formation. The tracer has been established to localize in tissues under chronic stress, specifically in cancer cells and neurodegenerative brain cells. A first-in-human imaging trial using positron emission tomography (PET) in cancer patients revealed unexpected tracer accumulation in the myocardium. Purpose: To describe human ¹²⁴I-PU-H71 myocardial biodistribution and pharmacokinetics in a series of cancer patients with no history of cardiovascular disease. Methods: 25 cancer patients (age 22–75 years, M:F − 7:18) with no history of cardiovascular disease received intravenous injections with microdose ¹²⁴I-PU-H71 while at rest, followed by dynamic and gated/non-gated PET image data acquisitions. Region-of-interest (ROI) analysis of left ventricular myocardium (LVmyo) and background left atrium quantified tracer concentrations as standardized uptake value (SUV) and uptake ratios. Kinetic rate constants were evaluated by a two-tissue compartment model. Results: Myocardial accumulation of ¹²⁴I-PU-H71 was prominent in all patients, with median LVmyo SUVmean (interquartile range, IQR) of 2.8 (IQR, 2.13–3.29), 2.5 (IQR, 1.94–2.98), 2.4 (IQR, 1.73–3.31) and 1.0 (IQR, 0.61–2.45), and median LVmyo/blood-pool ratios of 1.9 (IQR, 1.57–2.38), 2.0 (IQR, 1.53–2.32), 3.6 (IQR, 2.91–4.06) and 3.9 (IQR, 2.62–5.08) at 1–9 min, 14–23 min, 3–4 h and 21–25 h, respectively on non-gated PET images. Myocardium showed peak uptake within 2 min post-injection, with sustained myocardial tracer-concentration at 4 h post-injection. Pharmacokinetic modeling revealed median K₁ = 0.45 ml/min/g (IQR, 0.38–0.62); k₂ = 0.47 min^{− 1} (IQR, 0.27–0.71); k₃ = 0.16 min^{− 1} (IQR, 0.09–0.26); and k₄ = 0.0038 min^{− 1} (IQR, 0.0015–0.0057). Regional assessment demonstrated essentially uniform tracer uptake in LV and myocardial segments; with normal LVEF in all patients (mean 57.7 ± 3.5%); and no patients suffered cardiac events over subsequent 12-month period. Conclusion: Our study finds human myocardial epichaperome expression, as quantified by ¹²⁴I-PU-H71 PET. Our data indicates PU-H71 PET merits further study as a myocardial epichaperome biomarker, with potential application in drug development, possibly as a biomarker in subclinical cardiac dysfunction.