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

Abstract

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.

Keywords: Cancer and cardiovascular disease; Iodine-124; Myocardial imaging; PU-H71; Positron-emission tomography.

Fig. 1

Consecutive decay-corrected maximal intensity projection (MIP) PET images of a 57 year old woman with breast cancer injected with 200 MBq (5.4mCi) of radiotracer, demonstrating spatiotemporal whole-body distribution of 124I-PU-H71 at different time points. Patient with no history of cardiac disease showing tracer accumulation in myocardium (LV SUVmean 4.1, 3.9, 3.6, 3.3, and 1.4 at 5 min, 17 min, 30 min, 3 hrs, and 24 hrs, respectively) and visually distinct contrast between normal myocardium and other neighboring organs such as lung. Intense liver uptake shows decrease over time

Fig. 2

(A) Left ventricular input function Myocardium TAC averaged over 11 patients showing achievement of plateau within 2 minutes’ post-injection of ¹²⁴I-PU-H71. Blue time-activity curve (TAC) represents the total activity concentration as measured by PET, whereas red, green and grey TACs represent contributions of 1st compartment, 2nd compartment and combined 1st and 2nd compartments, respectively. (B) TAC representing the activity in combined 1st and 2nd compartments; initial peak due to first-pass tracer in blood excluded in the graph. (C) SUV for 3 different timepoints, for (i) myocardium (blue), (ii) lesions (black) and (iii) blood (red), suggestive of specific binding of radiotracer in both myocardium and lesions with a non-zero k₃; in addition, the SUV value at 4 h is higher compared to SUV at 30 min in the myocardium

Fig. 3

Short-axis, vertical long-axis and horizontal long-axis reconstructions of ¹²⁴I-PU-H71 myocardial PET data, in adult male patient with no cardiovascular risk factors. Images were acquired at 15 min (top rows) and 4 h (bottom rows) post-injection. At right, a polar map is shown