PT - JOURNAL ARTICLE AU - Stal Saurav Shrestha AU - Jeih-San Liow AU - Shuiyu Lu AU - Kimberly Jenko AU - Robert L. Gladding AU - Per Svenningsson AU - Cheryl L. Morse AU - Sami S. Zoghbi AU - Victor W. Pike AU - Robert B. Innis TI - <sup>11</sup>C-CUMI-101, a PET Radioligand, Behaves as a Serotonin 1A Receptor Antagonist and Also Binds to α<sub>1</sub> Adrenoceptors in Brain AID - 10.2967/jnumed.113.125831 DP - 2014 Jan 01 TA - Journal of Nuclear Medicine PG - 141--146 VI - 55 IP - 1 4099 - http://jnm.snmjournals.org/content/55/1/141.short 4100 - http://jnm.snmjournals.org/content/55/1/141.full SO - J Nucl Med2014 Jan 01; 55 AB - The PET radioligand 11C-CUMI-101 was previously suggested as a putative agonist radioligand for the serotonin 1A (5-hydroxytryptamine 1A [5-HT1A]) receptor in recombinant cells expressing human 5-HT1A receptor. However, a recent study showed that CUMI-101 behaved as a potent 5-HT1A receptor antagonist in rat brain. CUMI-101 also has moderate affinity (Ki = 6.75 nM) for α1 adrenoceptors measured in vitro. The current study examined the functional properties and selectivity of CUMI-101, both in vitro and in vivo. Methods: The functional assay was performed using 35S-GTPγS (GTP is guanosine triphosphate) in primate brains. The cross-reactivity of CUMI-101 with α1 adrenoceptors was performed using in vitro radioligand binding studies in rat, monkey, and human brains as well as in vivo PET imaging in mouse, rat, and monkey brains. Results: CUMI-101 did not stimulate 35S-GTPγS binding in primate brain, in contrast to 8-OH-DPAT, a potent 5-HT1A receptor agonist. Instead, CUMI-101 behaved as a potent 5-HT1A receptor antagonist by dose-dependently inhibiting 8-OH-DPAT–stimulated 35S-GTPγS binding. Both in vitro and in vivo studies showed that CUMI-101 had significant α1 adrenoceptor cross-reactivity. On average, across all 3 species examined, cross-reactivity was highest in the thalamus (&gt;45%) and lowest in the neocortex and cerebellum (&lt;10%). PET imaging further confirmed that only preblocking with WAY-100635 plus prazosin decreased 11C-CUMI-101 brain uptake to that of self-block. Conclusion: CUMI-101 behaves as a 5-HT1A receptor antagonist in primate brain, with significant, regional-dependent α1 adrenoceptor cross-reactivity, limiting its potential use as a PET radioligand in humans.