Kinetic Modeling, Test–Retest, and Dosimetry of ¹²³I-MNI-420 in Humans

Abstract

In vivo imaging of adenosine 2A receptors (A 2A ) in the brain has attracted significant interest from the scientific community, because studies have shown that dysregulation of these receptors is implicated in a variety of neurodegenerative and psychiatric disorders, including Parkinson and Huntington diseases. This work aimed to describe the kinetic properties, test-retest results, and dosimetry estimates of 123 I-MNI-420, a SPECT radiotracer for the in vivo imaging of A 2A in the brain. Methods: Nine healthy human subjects were enrolled in this study; 7 completed 123 I-MNI-420 brain SPECT studies, and 2 participated in whole-body planar imaging evaluating 123 I-MNI-420 biodistribution and dosimetry. For 3 of the brain SPECT studies, arterial blood was collected for invasive modeling. Noninvasive models were also explored, including Logan graphical analysis and simplified reference tissue models. Test-retest reliability was assessed in 4 subjects. To evaluate radiotracer biodistribution and dosimetry, serial whole-body images were acquired immediately after injection and at selected time points after injection. Urine samples were collected over a period of 21 h to calculate urinary excretion. Results: 123 I-MNI-420 rapidly entered the human brain and displayed uptake consistent with known A 2A densities. At pseudoequilibrium (reached at 90 min after radiotracer injection), stable target-to-cerebellum ratios of around 1.4-2.0 were determined. Binding potentials around 0.8-1.2 were estimated using different kinetic models and the cerebellum as the reference region. Average testretest variability in the striatum was 4.8%, 3.5%, and 6.5% for the simplified reference tissue model, Logan graphical analysis, and standardized uptake value ratio methods, respectively. The estimated radiation effective dose determined from whole-body studies was 0.036 mSv/MBq. Conclusion: The data indicate that 123 I-MNI-420 is a useful SPECT radiotracer for imaging A 2A in the brain and has radiation doses that would allow for multiple scans in the same research subject each year. The availability of 123 I-MNI-420 offers the possibility of investigating A 2A activity in specific conditions and evaluating drug occupancy for A 2A candidate therapeutics.

Characterization in Humans of 18F-MNI-444, a PET Radiotracer for Brain Adenosine 2A Receptors

“…For example, the highest BP ND values reported in human caudate and putamen for 11 C-SCH442416 and 11 C-TMSX were around 0.5-1.0 and 1.0-1.5, respectively (15,31,32). 18 F-MNI-444 also compares favorably with the iodinated SPECT analog 123 I-MNI-420, for which we have previously reported striatal BP ND values that ranged between 0.8 and 1.2 in the human brain (17).…”

“…Four subjects, 2 men and 2 women (mean age 6 SD, 28.3 6 7.5 y; range, 22-39 y), participated in the whole-body imaging studies of 18 F-MNI-444. All subjects were required to refrain from drinking caffeinated beverages for up to 12 h before the imaging session, given the known effect of caffeine on A 2A (16,17).…”

“…In 2011, Bhattacharjee et al developed 18 F-MRS5425, and preliminary data in rodents demonstrated that striatal binding was blocked by preadministration of the selective A 2A antagonist SCH442416 (10), but the potential utility of this radiotracer for imaging of A 2A in the human brain remains untested. Recently, we reported on the development of the first, to our knowledge, successful iodinated A 2A SPECT radiotracer, 123 I-MNI-420, both in nonhuman and human primates (16,17). Subsequently, we developed an analog of MNI-420 labeled with 18 F, 18 F-MNI-444.…”

“…The development of selective A 2A radiotracers would provide the opportunity to study and understand multiple neuropsychiatric and neurodegenerative disorders and could also accelerate and aid drug-discovery programs targeting A 2A . In this context, several compounds have been proposed for in vivo imaging of A 2A in the brain (6,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Preclinical Evaluation and Quantification of 18F-Fluoroethyl and 18F-Fluoropropyl Analogs of SCH442416 as Radioligands for PET Imaging of the Adenosine A2A Receptor in Rat Brain

“…Many studies have reported a dysregulation of A 2A receptor in neuropsychiatric disorders such as Parkinson, Huntington, and Alzheimer diseases; attention deficit hyperactivity and panic disorders; schizophrenia; pain; and impaired sleep (11). Several studies have suggested that the A 2A receptor may play an important role in the regulation of dopaminergic and glutamatergic neurotransmission in the basal ganglia through antagonistic interactions with the dopamine D 2 receptor and by forming functional heterodimers with metabotropic glutamate receptor 5, cannabinoid receptor type 1, and the adenosine A 1 receptor (12)(13)(14).…”