Development and evaluation of [¹²⁵I]IPPI for Tau imaging in postmortem human Alzheimer's disease brain

Abstract

Objective: Alzheimer's disease (AD) is a neurodegenerative disease characterized by aggregation of Tau protein into paired helical filaments causing neurofibrillary tangles (NFT) in the brain. The aim of this study was to develop and evaluate the effectiveness of a novel radioiodinated tracer, 6‐[125I]iodo‐3‐(1H‐pyrrolo[2,3‐c]pyridine‐1‐yl)isoquinoline ([125I]IPPI), for binding to Tau protein (Ki = 0.75 nM) in postmortem human brain (AD and cognitively normal (CN). Methods: Radiosynthesis of [125I]IPPI was carried out by radioiododestannylation and purified chromatographically. Computational modeling studies of IPPI and MK‐6240 binding on Tau fibril were evaluated. In vitro autoradiography studies were carried out with [3H]PIB for Aβ plaques and [125I]IPPI for Tau in AD and CN brains and evaluate drug effects. Results: [125I]IPPI was produced in >95% purity. Molecular modeling of IPPI revealed binding energies of IPPI (−7.8, −8.1, −8.2, −7.5 Kcal/mol) at the four sites were comparable to MK‐6240 (−8.7, −8.5, −8.3, −7.5 Kcal/mol). Ratio of average grey matter (GM) [125I]IPPI in AD versus CN was found to be 7.31 (p = .07) and AD GM/ white matter (WM) = 4.35 (p = .09). Ratio of average GM/WM [125I]IPPI in CN was 1.21. Binding of [125I]IPPI correlated with the presence of Tau, confirmed by anti‐Tau Dako A0024. Specifically bound [125I]IPPI to Tau in AD brains was displaced by MK‐6240 and IPPI (>90%). Monoamine oxidase inhibitors (MAO) inhibitors deprenyl and clorgyline effected [125I]IPPI binding at >1 µM concentrations. Conclusion: [125I]IPPI exhibited high binding in human AD frontal cortex and anterior cingulate and is a suitable radioiodinated ligand for Tau imaging.

Elevated Monoamine Oxidase-A in Anterior Cingulate of Post-Mortem Human Parkinson’s Disease: A Potential Surrogate Biomarker for Lewy Bodies?

“…Ratio of PD GM/CN GM = 2.78, indicating >200% increase in PD, while average GM/WM = 2.18 for all CN subjects and average GM/WM = 3.15 for all PD subjects, suggesting a 45% increase in PD using ratios, which is more relevant to in vivo imaging where typically a reference region for quantification. All PD subjects showed lack of [ 18 F]flotaza binding [ 30 ] confirming absence of Aβ plaques, and absence of [ 125 I]IPPI binding [ 31 ], confirming absence of neurofibrillary tangles (NFT). Thus, an increase in MAO-A in the anterior cingulate of PD brains compared to CN brains was observed.…”

[124I]IBETA: A New Aβ Plaque Positron Emission Tomography Imaging Agent for Alzheimer’s Disease

“…Sodium iodide, [ 124 I]NaI (3D Imaging LLC) and [ 125 I]NaI (ARC Inc.) were used to prepare [ 124 I]IBETA and [ 125 I]IBETA by the electrophilic substitution of the tributyltin derivative using reported radioiodination methods [ 21 , 22 ]. The radiosynthesis of [ 124 I]IBETA using methods modified from [ 22 ] and [ 125 I]IBETA using methods modified from [ 15 , 16 ] were successfully caried out.…”

Development of [124/125I]IAZA as a New Proteinopathy Imaging Agent for Alzheimer’s Disease

“…In the case of Tau, increasing concentrations of IAZA (1 nM to 10 μM) had a lower effect on the binding of [ 125 I]IPPI, with 10 μM IAZA displacing about 50% of [ 125 I]IPPI bound to Tau, as shown in Figure 2 F. An IC 50 = 8.65 μM was measured for IAZA binding to Tau. Using the affinity of [ 125 I]IPPI (0.75 nM [ 17 ]), the binding affinity Ki of IAZA for Tau was calculated to be 3.71 μM.…”

“…Upon the addition of Aβ-plaque-binding drugs (10 μM each), IAZA and BrBETA [ 15 ], more than 95% of [ 125 I]IAZA binding to Aβ plaques was displaced, suggesting a high affinity for Aβ binding sites ( Figure 4 , IAZA and BrBETA). The Tau agents MK-6240 and IPPI [ 17 ] at 10 μM concentrations reduced the binding to approximately 55%. Similarly, MAO inhibitors clorgyline for MAO-A and deprenyl for MAO-B at 10 μM concentrations reduced the binding of [ 125 I]IAZA to approximately 65% of the total binding.…”

“…Our recent work on the selective azaindole [ 125 I]IPPI ( Figure 1 , 2 ) for imaging human Tau NFT shows promise as a potential agent for SPECT imaging when labeled with iodine-123. [ 17 ].…”