1. We found that 18F-FIMX was successfully able to quantify metabotropic glutamate receptor 1 (mGluR1) in human brain, and that correlation of brain uptake with the relative density of mGluR1 transcript allowed specific receptor binding of a radioligand to be quantified without injecting pharmacological doses of a blocking agent. Work performed under NCT02230592. mGluR1 has been linked to the pathophysiology of several neurological and psychiatric disorders. We previously developed the only radioligand 18F-FIMX for successful imaging of the mGluR1 receptor in human brain. Our initial investigation found that 18F-FIMX provided excellent imaging of mGluR1s in monkey brain. Expanding this work, we used 18F-FIMX in a first-in-human PET imaging study. We also sought to use the relative density of mGluR1 gene transcripts in brain regions to estimate specific and nondisplaceable uptake in each brain region. After injection of 18F-FIMX, 12 healthy volunteers underwent a dynamic PET scan over 120 minutes. In six of them, images were acquired until 210 min. Four other subjects had whole-body scans to estimate radiation exposure. We found that 18F-FIMX uptake into human brain was high, peaked at about 10 min, and washed out rapidly. An unconstrained two-tissue compartment model fitted the data well, and VT (mLcm-3) values ranged from 1.5 in caudate to 11 in cerebellum. A 120-min scan provided stable VT values in all regions except the cerebellum, for which an acquisition time of at least 170 min was necessary. VT values in brain regions correlated well with mGluR1 transcript density, and the correlation suggested that the nondisplaceable uptake (VND) of 18F-FIMX was quite low. Similar to other 18F-labeled ligands, the effective dose was about 23 Sv/MBq. Thus, 18F-FIMX had high brain uptake in human brain and washed out quickly enough to measure mGluR1 within 120-170 min. The nonspecific binding of 18F-FIMX was quite small, and a low receptor density region like caudate may function as a pseudo-reference region, thereby avoiding arterial blood sampling. Together, the results suggest that 18F-FIMX can quantify mGluR1 in human brain, and correlation of brain uptake with the relative density of mGluR1 transcript allows specific receptor binding of a radioligand to be quantified without injecting pharmacological doses of a blocking agent. 2. We found that to measure translocator protein (TSPO) density in Alzheimers Disease (AD) and control subjects, a simple ratio method (standardized uptake value ratio, SUVR) can substitute for, and may even be more sensitive than, absolute quantitation. We also found that TSPO binding increases with progression of AD but not in healthy aging, suggesting that inflammation increases in proportion to worsening of disease in AD. Work performed under NCT00613119 and NCT00955422. For several years, we have been working to identify putative biomarkers of inflammatory changes in brain. AD is associated with increased brain levels of TSPO, which is over-expressed in activated microglia and reactive astrocytes. Measuring the density of TSPO with PET typically requires absolute quantitation with arterial blood sampling, because no reference region devoid of TSPO exists in brain. We investigated whether a simple ratio method could substitute for absolute quantitation of binding with 11C-PBR28, a second generation radioligand for TSPO. 11C-PBR28 PET imaging was performed in 21 healthy controls, 11 individuals with mild cognitive impairment (MCI), and 25 AD patients. Group differences in 11C-PBR28 binding were compared using two methods: the gold standard method of calculating VT, using the two-tissue compartmental model with the arterial input function corrected for plasma free fraction of radiotracer and a ratio of brain uptake in target regions to that in cerebellum: SUVR. Using absolute quantitation, we confirmed that TSPO binding: 1) was greater in AD patients than healthy controls in expected temporo-parietal regions, and 2) was not significantly different among the three groups in cerebellum. Using the cerebellum as a pseudo-reference region, the SUVR method detected greater binding in AD patients than controls in the same regions as absolute quantification and in one additional region, suggesting that SUVR may have greater sensitivity. The results indicate that, to measure TSPO density in AD and control subjects, a simple ratio method (SUVR) can substitute for, and may even be more sensitive than, absolute quantitation. This method is expected to improve subject tolerability by allowing shorter scan time and not requiring arterial catheterization. It may also allow smaller sample sizes for comparable statistical significance because of the relatively low variability of the ratio values. We then sought to determine if TSPO binding increases with progression of AD and in healthy aging. Eleven patients with either AD or MCI and eight cognitively normal age-matched controls underwent 11C-PBR28 PET at baseline and after median follow-up of 2.7 years. Cerebellar gray matter was used as a pseudo-reference region. For patients, 11C-PBR28 binding in target regions was 2.517% greater at follow-up than baseline, with greatest increase in entorhinal cortex. For controls, regional binding at follow up was within 5% of baseline values. Change in Clinical Dementia Rating scale score also correlated with change in 11C-PBR28 binding in several brain regions. Together, the results show that TSPO binding increased with progression of AD but not in healthy aging. These results suggest that inflammation increases in proportion to worsening of disease in AD and that 11C-PBR28 PET may be useful for measuring disease progression. 3. Using 11C-(R)-rolipram, a phosphodiesterase type IV (PDE4) inhibitor, we found that two months of treatment with an SSRI increased (normalized) PDE4 binding in individuals with MDD. Work performed under NCT00369798. PDE4 is an important component of the cyclic adenosine monophosphate (cAMP) cascade, and studies suggest that it mediates the effects of several antidepressants. We previously confirmed in animals that increased 11C(R)-rolipram binding reflects the phosphorylated/active state of PDE4. Using this radioligand, we found that PDE4 binding was decreased in unmedicated patients with MDD, consistent with the cAMP theory of depression. To quantify the binding of 11C-(R)-rolipram as an indirect measure of this enzyme's activity in the brain of individuals with MDD, we performed 11C-(R)-rolipram brain PET scans in 28 moderately depressed MDD subjects and 25 age- and gender-matched healthy controls; roughly half of the patients were treatment-naive. PDE4 levels were decreased in unmedicated individuals with MDD in vivo. In collaboration with Dr. Zarate (NIMH), we explored whether antidepressant treatment upregulates PDE4 in humans. In this recently completed study, 23 of the 43 unmedicated MDD patients had a follow-up rolipram scan after starting treatment with SSRIs. Patients showed an increase of 11% (P<0.0001) in rolipram binding after SSRI treatment (mostly citalopram) across 10 large brain regions. In contrast, 11 healthy controls who had a repeat scan without SSRI showed only small changes on repeat scans. For patients, significant negative correlations were seen in all regions, and patients with lower baseline rolipram binding showed greater increases after SSRI treatment. Older patients showed significantly greater increases in post-SSRI rolipram binding. The results suggest that the cAMP cascade, as indirectly measured with PDE4 binding, is downregulated in unmedicated patients with MDD, and that antidepressant treatment normalizes this 11C(R)-rolipram downregulation. This suggests that PDE4 inhibition, perhaps via subtype selective agents, might again be assessed for efficacy in MDD.
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