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

Abstract

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, [ 68 Ga]Ga-NOTA-insulin, to noninvasively study the role of insulin in AD. The developed PET probe [ 68 Ga]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, [ 68 Ga]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 [ 68 Ga]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 [ 68 Ga]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 [ 68 Ga]Ga-NOTA-insulin into the brain using MicroPET imaging data and supported the in vivo results. The [ 68 Ga]Ga-NOTA-insulin PET probe was successfully synthesized and evaluated in a mouse model of AD in comparison with [ 18 F]AV1451 and [ 11 C]PIB to noninvasively study the role of insulin in AD pathophysiology.

Deconvolution of plasma pharmacokinetics from dynamic heart imaging data obtained by SPECT/CT imaging

“…Successful application of the modeling method established in this study, will allow us to infer distribution kinetics of other tracers in both health and disease. Indeed, we have employed this approach to evaluate blood-to-brain influx of a newly developed PET probe 68 Ga-NOTA-insulin in wild type and Alzheimer’s transgenic mice (Taubel, Nelson et al. ).…”

Evidence for an alternative insulin transporter at the blood-brain barrier

“…Since then, others have supported this finding, showing inhibition of the BEC insulin receptor did not impact insulin transport in an in vitro model [50] and in mice [48]. In an exciting new paper describing a novel, in vivo insulin PET tracer, co-administration of S961 also had no effect on brain insulin uptake in mice [49]. These data suggest there is another protein(s) responsible for transporting insulin across the BEC.…”

“…There have also been factors and/or states that have had no effect on insulin transport. Most surprisingly, the loss or inhibition of the BEC insulin receptor had no effect on insulin transport [43,[48][49][50]. We have summarized this literature in Table 1 and refer readers to the specific references mentioned for each factor/disease state/intervention investigated.…”

The Reduced Gray Matter Volume and Functional Connectivity of the Cerebellum in Type 2 Diabetes Mellitus with High Insulin Resistance

“…Recent studies have found that cerebellar atrophy was associated with insulin resistance and poorer performance on cognitive tests assessing of verbal memory recognition and executive function in older adults with dysglycemia [20]. Moreover, elevated insulin uptake in the cerebellum of Alzheimer's disease rats has been observed [21]. However, it remains unclear whether changes in the cerebellum are related to insulin resistance and how they may further impact the cognitive-emotional functions of T2DM patients.…”