Lars Farde

Background: We recently published putative in vivo maps of GABA _A receptor subtypes—α ₁ /α ₃ , α ₂ , and α ₅ . Here we tested how these maps align with functional anatomical cortical areas and large-scale functional networks. Methods: Cortical α subunit maps were projected to the symmetric fs_LR template and compared with the Human Connectome Project multi‑modal parcellation. Congruence was assessed by visual inspection, within‑parcel variability, and the distance‑controlled boundary coefficient (DCBC) with spin‑permutation null models. Subunit profiles were summarized per cortical area and related to functional networks. Results: Inspection revealed conspicuous congruence between α -subunit distributions and areal boundaries. α ₁ /α ₃ subunits predominated in primary sensory/motor areas, α ₂ peaked in neighboring secondary areas and α ₅ was concentrated in cingulo-opercular and insular areas. Within‑parcel variability was low, and congruence was supported by a positive, significant DCBC (0.1065, p -spin = 0.0006) exceeding the random parcellation. Large‑scale networks showed characteristic subunit combinations: functionally “narrow” networks were subunit-predominant, while associative networks clustered around mixed patterns away from extremes. Conclusion: Cortical GABA _A receptor α subunit distributions align with multimodal areas and display network‑specific profiles, linking inhibitory chemiarchitectonics to cortical organization. The present analysis supports integration of molecular with structural and functional imaging for extended understanding of human brain function. ClinicalTrials.gov: NCT00681720 and NCT00681746

Background: AZD2423 is a high-affinity and selective negative allosteric modulator of the chemokine receptor type 2 (CCR2). This receptor plays important roles in the extravasation and transmigration of monocytes under inflammatory conditions. The aims of the current positron emission tomography (PET) study were as follows: (i) to develop an efficient synthetic method for labeling AZD2423 with carbon-11 (¹¹C, t_1/2 = 20.4 min) and (ii) to evaluate its potential to visualize CCR2 binding in the non-human primate (NHP) brain. Methods: [¹¹C]AZD2423 was synthesized using a novel two-step, two-pot [¹¹C]carbon monoxide carbonylation procedure. PET imaging studies in NHPs (n = 2) were conducted to assess its brain penetration and in vivo distribution. Results: Radiolabeling of [¹¹C]AZD2423 was accomplished with good yield (7.4 ± 0.6%, n = 4) and high radiochemical purity (>99%) using [¹¹C]carbon monoxide. Preliminary PET imaging in NHPs revealed low [¹¹C]AZD2423 brain exposure under both baseline and pretreatment conditions (SUV_peak = 0.4, n = 2). However, high concentrations of radioactivity were observed in organs outside the brain at baseline, e.g., the thyroid gland (SUV_peak = 3.3, n = 2), parotid gland (SUV_peak = 3.4, n = 2), and submandibular gland (SUV_peak = 4.4, n = 2). This radioactivity was markedly reduced following pretreatment with AZD2423 (3.0 mg/kg), indicating specific binding of [¹¹C]AZD2423 to CCR2 in vivo. The presence of specific CCR2 binding was further validated using two-tissue compartment modeling, which demonstrated a 59–63% reduction in the total volume of distribution values in the analyzed peripheral tissues. Conclusions: Altogether, [¹¹C]AZD2423 shows potential as a PET radioligand for the in vivo visualization of CCR2 expression in tissues outside the brain and may also serve as a lead compound for the further development of a CCR2 PET radioligand suitable for brain imaging.

Supplementary Figure S1 - Structure and position of label for compounds assessed for BBB penetrance in non human primates (NHP). Majority of compounds were labelled with carbon-11 except afatinib which was labelled with fluorine-18. (*) Indicates position for carbon-11 label

Purpose:Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood–brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy.Experimental Design:We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in vitro and in vivo BBB preclinical models.Results:In vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In vivo rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (Cmax %ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionization mass spectroscopy images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib with the poorly BBB penetrant afatinib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth.Conclusions:These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. This work also demonstrates the link between low in vitro transporter efflux ratios and increased brain penetrance in vivo supporting the use of in vitro transporter assays as an early screen in drug discovery.

Purpose:Osimertinib is a potent and selective EGFR tyrosine kinase inhibitor (EGFR-TKI) of both sensitizing and T790M resistance mutations. To treat metastatic brain disease, blood–brain barrier (BBB) permeability is considered desirable for increasing clinical efficacy.Experimental Design:We examined the level of brain penetration for 16 irreversible and reversible EGFR-TKIs using multiple in vitro and in vivo BBB preclinical models.Results:In vitro osimertinib was the weakest substrate for human BBB efflux transporters (efflux ratio 3.2). In vivo rat free brain to free plasma ratios (Kpuu) show osimertinib has the most BBB penetrance (0.21), compared with the other TKIs (Kpuu ≤ 0.12). PET imaging in Cynomolgus macaques demonstrated osimertinib was the only TKI among those tested to achieve significant brain penetrance (Cmax %ID 1.5, brain/blood Kp 2.6). Desorption electrospray ionization mass spectroscopy images of brains from mouse PC9 macrometastases models showed osimertinib readily distributes across both healthy brain and tumor tissue. Comparison of osimertinib with the poorly BBB penetrant afatinib in a mouse PC9 model of subclinical brain metastases showed only osimertinib has a significant effect on rate of brain tumor growth.Conclusions:These preclinical studies indicate that osimertinib can achieve significant exposure in the brain compared with the other EGFR-TKIs tested and supports the ongoing clinical evaluation of osimertinib for the treatment of EGFR-mutant brain metastasis. This work also demonstrates the link between low in vitro transporter efflux ratios and increased brain penetrance in vivo supporting the use of in vitro transporter assays as an early screen in drug discovery.

Supplementary Figure S1 - Structure and position of label for compounds assessed for BBB penetrance in non human primates (NHP). Majority of compounds were labelled with carbon-11 except afatinib which was labelled with fluorine-18. (*) Indicates position for carbon-11 label

Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib is a third-generation, irreversible, EGFR-tyrosine kinase inhibitor that potently and selectively inhibits EGFR-sensitizing and T790M resistance mutations with efficacy in EGFRm NSCLC including central nervous system (CNS) metastases. The open-label phase I positron emission tomography (PET) and magnetic resonance imaging (MRI) study (ODIN-BM) assessed [C-11]osimertinib brain exposure and distribution in patients with EGFRm NSCLC and BMs. Three dynamic 90-min [C-11]osimertinib PET examinations were acquired together with metabolite-corrected arterial plasma input functions at: baseline, after first oral osimertinib 80 mg dose, and after greater than or equal to 21 days of osimertinib 80 mg q.d. treatment. Contrast-enhanced MRI was performed at screening and after 25-35 days of osimertinib 80 mg q.d.; treatment effect was assessed per CNS Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and per volumetric changes in total BM using a novel analysis approach. Four patients (aged 51-77 years) completed the study. At baseline, similar to 1.5% injected radioactivity reached the brain (IDmax[brain]) 22 min (median, T-max[brain]) after injection. Total volume of distribution (V-T) in whole brain was numerically higher compared with the BM regions. After a single oral osimertinib 80 mg dose, there was no consistent decrease in V-T in whole brain or BMs. After greater than or equal to 21 days' daily treatment, V-T in whole brain and BMs were numerically higher versus baseline. MRI revealed 56%-95% reduction in total BMs volume after 25-35 days of osimertinib 80 mg q.d. treatment. The [C-11]osimertinib crossed the blood-brain and brain-tumor barriers and had a high, homogeneous brain distribution in patients with EGFRm NSCLC and BMs. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Brain metastases (BMs) are associated with poor prognosis in epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). Osimertinib has demonstrated efficacy in EGFRm NSCLC, including central nervous system metastases. However, the exposure and exact distribution of osimertinib in whole brain following administration in patients with BMs is unknown. WHAT QUESTION DID THIS STUDY ADDRESS? ODIN-BM was a phase I multimodal imaging study combining positron emission tomography (PET) and magnetic resonance imaging to examine osimertinib brain exposure in patients with EGFRm NSCLC and BMs. The results demonstrated homogenous distribution of radiolabeled osimertinib in the whole brain and BMs. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? These findings corroborate preclinical data and observations in healthy volunteers with an intact blood brain barrier to patients with BMs treated with osimertinib. Notably, our study demonstrated that presence of [C-11]osimertinib exposure in BMs shell and core regions was similar to that in the surrounding brain tissue, suggesting that [C-11]osimertinib passes the blood-brain and blood-tumor barriers. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Findings of this study offer more information regarding osimertinib brain exposure and its radiologically assessed efficacy in BMs as reported in large clinical trials and recent case study reports. Data suggesting that [C-11]osimertinib passes the blood-brain and brain-tumor barriers has not been reported with any other anticancer treatment to the best of our knowledge. Additionally, this study also illustrates the potential of microdosing PET studies in the development of drugs targeting brain malignancies.

Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [¹¹C]FLB457. The main outcome was D2-R binding potential (BP_ND) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen’s dz = −0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BP_ND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen’s dz = −0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen’s d = −0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity.