In Vivo PET Imaging of [ ¹⁸ F]CHDI-385, a Radioligand for Mutant Huntingtin Aggregates in a Mouse Model of Huntington Disease

Aggregation of mutant huntingtin (mHTT) is a neurologic hallmark of Huntington disease (HD), a neurodegenerative disorder caused by the expansion of a cytosine-adenine-guanine repeat tract in the huntingtin gene (<i>HTT</i>). With a considerable number of candidate therapeutic interventions aimed at lowering mHTT expression under investigation, noninvasive monitoring of changes in mHTT aggregate levels in the brain could hasten the development and identification of disease-modifying therapies. Here we evaluate a new radioligand, [¹⁸F]CHDI-385, to quantify mHTT aggregates using microPET imaging in the zQ175DN mouse model of HD. <b>Methods:</b> In 3- and 9-mo old wild-type (<i>n</i> = 24 for each age) and heterozygous zQ175DN (<i>n</i> = 24 for each age) mice, we assessed the plasma and brain radiometabolite profile, explored in vivo tracer kinetics (including test-retest variability), and performed quantitative (using total volume of distribution based on a noninvasive image-derived input function, 0-120 min) and semiquantitative (using SUV; time interval, 100-120 min after injection) analyses to determine the performance of this radioligand in detecting mHTT aggregates in vivo. <b>Results:</b> [¹⁸F]CHDI-385 showed metabolic stability in both wild-type and heterozygous mice as well as sufficient cerebral retention time in both genotypes. Quantitative (2-tissue compartmental model and Logan graphical analysis) and semiquantitative (SUV) analyses were in strong agreement with one another (striatum, <i>r²</i> = 0.986; <i>P</i> < 0.0001). Differences in measures of [¹⁸F]CHDI-385 uptake were significant between heterozygous mice and wild-type mice at both 3 mo (<i>P</i> < 0.001) and 9 mo (<i>P</i> < 0.0001). In addition, [¹⁸F]CHDI-385 displayed a good to excellent test-retest variability as indicated by the intraclass correlation coefficient (ICC) with both quantitative (ICC, 0.62-0.78) and semiquantitative (ICC, 0.65-0.80) analyses. <b>Conclusion:</b> [¹⁸F]CHDI-385 demonstrated excellent kinetics and reliable semiquantitative and quantitative performance. Importantly, the validation of semiquantitative analysis supports the use of the more clinically friendly SUV metric, which does not require the use of an input function and metabolite correction. These results indicate that [¹⁸F]CHDI-385 is a radioligand with optimal properties for detecting and quantifying cerebral mHTT aggregates and support its clinical evaluation.