[en] Exploring synaptic density changes during brain growth is crucial to understanding brain development. Previous studies in nonhuman primates report a rapid increase in synapse number between the late gestational period and the early neonatal period, such that synaptic density approaches adult levels by birth. Prenatal synaptic development may have an enduring impact on postnatal brain development, but precisely how synaptic density changes in utero are unknown because current methods to quantify synaptic density are invasive and require post-mortem brain tissue. We used synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) radioligands [${}^{11}$C]UCB-J and [${}^{18}$F]Syn-VesT-1 to conduct the first assessment of synaptic density in the developing fetal brain in gravid rhesus monkeys. Eight pregnant monkeys were scanned twice during the third trimester at two imaging sites. Fetal post-mortem samples were collected near term in a subset of subjects to quantify SV2A density by Western blot. Image-derived fetal brain SV2A measures increased during the third trimester. SV2A concentrations were greater in subcortical regions than in cortical regions at both gestational ages. Near term, SV2A density was higher in primary motor and visual areas than respective associative regions. Post-mortem quantification of SV2A density was significantly correlated with regional SV2A PET measures. While further study is needed to determine the exact relationship of SV2A and synaptic density, the imaging paradigm developed in the current study allows for the effective in vivo study of SV2A development in the fetal brain.

[en] Objectives: The α_vβ₃ integrin is a cell adhesion molecule known to be involved in stages of angiogenesis and metastasis. In this study, the chelators CB-TE2A and diamsar were conjugated to cyclic RGDyK and RGDfD and the biological properties of ⁶⁴Cu-labeled peptides were compared. Methods: CB-TE2A-c(RGDyK) and diamsar-c(RGDfD) were labeled with ⁶⁴Cu in 0.1 M NH₄OAc (pH=8) at 95^oC and 25^oC, respectively. PET and biodistribution studies were carried out on M21 (α_vβ₃-positive) and M21L (α_v-negative) melanoma-bearing mice. Binding affinity of the Cu-chelator-RGD peptides to α_vβ₃ integrins was determined by a competitive binding affinity assay. Results: Biological studies showed higher concentration of ⁶⁴Cu-CB-TE2A-c(RGDyK) in M21 tumor compared to M21L tumor at 1 and 4 h pi. Tumor concentration of ⁶⁴Cu-CB-TE2A-c(RGDyK) was higher than that of ⁶⁴Cu-diamsar-c(RGDfD). The difference is not due to differing binding affinities, since similar values were obtained for the agents. Compared to ⁶⁴Cu-diamsar-c(RGDfD), there is more rapid liver and blood clearance of ⁶⁴Cu-CB-TE2A-c(RGDyK), resulting in a lower liver and blood concentration at 24 h pi. Both ⁶⁴Cu-labeled RGD peptides show similar binding affinities to α_vβ₃. The differences in their biodistribution properties are likely related to different linkers, charges and lipophilicities. The M21 tumor is clearly visualized with ⁶⁴Cu-CB-TE2A-c(RGDyK) by microPET imaging. Administration of c(RGDyK) as a block significantly reduced the tumor concentration; however, the radioactivity background was also decreased by the blocking dose. Conclusions: Both ⁶⁴Cu-CB-TE2A-c(RGDyK) and ⁶⁴Cu-diamsar-c(RGDfD) are potential candidates for imaging tumor angiogenesis. For diamsar-c(RGDfD), a linker may be needed between the Cu-chelator moiety and the RGD peptide to achieve optimal in vivo tumor concentration and clearance from nontarget organs.