Design, Synthesis, and Preliminary Evaluation of [⁶⁸Ga]Ga-NOTA-Insulin as a PET Probe in an Alzheimer’s Disease Mouse Model

Aberrant insulin signaling has been considered one of the risk factors for the development of Alzheimer’s disease (AD) and has drawn considerable attention from the research community to further study its role in AD pathophysiology. Herein, we describe the development of an insulin-based novel positron emission tomography (PET) probe, [⁶⁸Ga]Ga-NOTA-insulin, to noninvasively study the role of insulin in AD. The developed PET probe [⁶⁸Ga]Ga-NOTA-insulin showed a significantly higher uptake (0.396 ± 0.055 SUV) in the AD mouse brain compared to the normal (0.140 ± 0.027 SUV) mouse brain at 5 min post injection and also showed a similar trend at 10, 15, and 20 min post injection. In addition, [⁶⁸Ga]Ga-NOTA-insulin was found to have a differential uptake in various brain regions at 30 min post injection. Among the brain regions, the cortex, thalamus, brain stem, and cerebellum showed a significantly higher standard uptake value (SUV) of [⁶⁸Ga]Ga-NOTA-insulin in AD mice as compared to normal mice. The inhibition of the insulin receptor (IR) with an insulin receptor antagonist peptide (S961) in normal mice showed a similar brain uptake profile of [⁶⁸Ga]Ga-NOTA-insulin as it was observed in the AD case, suggesting nonfunctional IR in AD and the presence of an alternative insulin uptake route in the absence of a functional IR. The Gjedde-Patlak graphical analysis was also performed to predict the input rate of [⁶⁸Ga]Ga-NOTA-insulin into the brain using MicroPET imaging data and supported the in vivo results. The [⁶⁸Ga]Ga-NOTA-insulin PET probe was successfully synthesized and evaluated in a mouse model of AD in comparison with [¹⁸F]AV1451 and [¹¹C]PIB to noninvasively study the role of insulin in AD pathophysiology.